News

Headline

ZTGC: bacteriophages reinvent the DNA alphabet

In 1977, Kirnos et al. isolated a DNA virus acting on blue-green algae, called cyanophage S-2L, from water samples taken in the outskirts of Leningrad (known today as Saint Petersburg). They reported a weird DNA composition for this virus. Instead of the usual adenine (6-aminopurine or A), the bacteriophage contained 2,6-diaminopurine (DAP), also known as 2-aminoadenine, abbreviated Z in recent publications. The presence of the additional amino group in adenine changes several DNA features. The most striking difference is that DAP forms 3 hydrogen bonds when paired with thymine, instead of the usual 2 bonds between adenine and thymine, hence forming a stronger, more stable pair. The presence of DAP confers selective advantages to bacteriophages, such as resistance to most restriction enzymes. Consequently, these viruses can evade the host bacterial defense system based on foreign DNA degradation.

In view of the complete substitution of adenine by DAP, Kirnos et al. proposed that DAP was incorporated into S-2L phage DNA as a ready-made nucleotide, rather than formed at the polynucleotide level as a result of amination of adenine residues within DNA. However, it took almost half a century to unravel the pathway of DAP synthesis and its incorporation into DNA. This pathway intermingles viral and bacterial enzymes in tight collaboration. The first step of DAP synthesis involves the condensation of aspartate with deoxyguanylate to form N6-succino-2-amino-2'-deoxyadenylate (dSMP). The reaction is catalyzed by phage PurZ. dSMP is then converted into 2-amino-2'-deoxyadenosine monophosphate (dZMP) by an enzyme encoded by purB. dZMP is further phosphorylated by guanylate kinase (gmk) and by nucleoside diphosphate kinase (ndk) to produce 2-amino-2'-deoxyadenosine-5'-triphosphate (dZTP). All three enzymes, encoded by the purB, gmk and ndk genes, are provided by the bacterial host. dZTP is incorporated into phage DNA by viral DpoZ polymerase, which shares similarity with the Klenow fragment of Escherichia coli DNA polymerase I. The selective incorporation of dZTP rather than dATP into phage DNA is still a matter of debate. Pezo et al. showed that DpoZ has a strong preference for dZTP over dATP. However, Czernecki and Zhou proposed another mechanism of dATP exclusion, in which another phage enzyme, a dATPase called DatZ, would break up dATP, while preserving dZTP. The removal of dATP (and of its precursor dADP) from the nucleotide pool of the host would prevent the incorporation of adenine into the phage genome.

If cyanophage S-2L looked like a strange outlier 50 years ago, nowadays its amazing DNA composition appears to be more widespread than anticipated. PurZ has been identified in over a hundred bacteriophages, that infect a variety of microorganisms, including cyanobacteria, proteobacteria and actinobacteria, and the presence of Z-genomes have been experimentally proven in several of them. DAP usage to convey genetic information may be ancient. Phylogenic trees of PurZ and DpoZ indicate that DAP may have been used among siphoviruses since the evolutionary divergence of actinobacteria, cyanobacteria, and proteobacteria some 3.5 billion years ago. Moreover DAP, along with other nucleobases, has been found in meteorites, suggesting it could have been available before the advent of life for constructing the first genetic molecules.

As of this release, representative entries for the proteins involved in viral Z-genome manufacturing have been manually annotated and are publicly available. These entries include viral PurZ, DNA polymerase DpoZ and dATPase DatZ and bacterial PurB, Gmk and Ndk. Viral PurZ proteins can also be identified with a newly created HAMAP family profile.

It should be noted that DAP has been first abbreviated 'D', but more recently the abbreviation 'Z' took over and DNA containing this nucleotide was called 'Z-DNA'. This latter nomenclature may be misleading. The term 'Z-DNA' classically refers to a specific left-handed double helical structure in which the helix winds to the left in a zigzag pattern, instead of to the right, like the more common B-DNA form. This type of structure does not contain 2,6-diaminopurine.

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Alzahrani-Kuwahara syndrome
• Arthrogryposis multiplex congenita 6
• Azoospermia, obstructive, with nephrolithiasis
• Baralle-Macken syndrome
• Bartsocas-Papas syndrome 2
• Bile acid conjugation defect 1
• Bleeding disorder, platelet-type, 24
• Blepharophimosis-impaired intellectual development syndrome
• Buratti-Harel syndrome
• Cataracts, spastic paraparesis, and speech delay
• Coffin-Siris syndrome 12
• Dysostosis multiplex, Ain-Naz type
• CIMDAG syndrome
• Deafness, autosomal dominant, 80
• Developmental and epileptic encephalopathy 6B
• Developmental and epileptic encephalopathy 96
• Developmental delay with dysmorphic facies and dental anomalies
• Dystonia 30
• Fibromuscular dysplasia, multifocal
• Glanzmann thrombasthenia 2
• Global developmental delay with speech and behavioral abnormalities
• Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
• Hiatt-Neu-Cooper neurodevelopmental syndrome
• Hypercholanemia, familial, 2
• Immunodeficiency 14B, autosomal recessive
• Immunodeficiency 77
• Immunodeficiency 78 with autoimmunity and developmental delay
• Immunodeficiency 79
• Immunodeficiency 80 with or without congenital cardiomyopathy
• Intellectual developmental disorder, autosomal dominant 65
• Intellectual developmental disorder and hypogonadotropic hypogonadism
• Juberg-Hayward syndrome
• KINSSHIP syndrome
• Kohlschutter-Tonz syndrome-like
• Leukodystrophy, hypomyelinating, 21
• Leukodystrophy, hypomyelinating, 22
• Lymphatic malformation 9
• Mahvash disease
• Marbach-Rustad progeroid syndrome
• Megacystis-microcolon-intestinal hypoperistalsis syndrome 2
• Megaloblastic anemia, folate-responsive
• Microcephaly, epilepsy, and diabetes syndrome 2
• Mitochondrial complex I deficiency, nuclear type 37
• Nephrotic syndrome 24
• Neurodegeneration with ataxia and late-onset optic atrophy
• Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism
• Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction
• Neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia
• Neurodevelopmental disorder with dysmorphic facies and variable seizures
• Neurodevelopmental disorder with or without autism or seizures
• Neurodevelopmental disorder with seizures and gingival overgrowth
• Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia
• Oculogastrointestinal neurodevelopmental syndrome
• Ondontochondrodysplasia 2 with hearing loss and diabetes
• Parkinsonism with polyneuropathy
• Pontocerebellar hypoplasia 14
• Pontocerebellar hypoplasia 15
• Pontocerebellar hypoplasia 1E
• Pontocerebellar hypoplasia 1F
• Premature ovarian failure 19
• Radio-Tartaglia syndrome
• Roifman-Chitayat syndrome
• Short stature, oligodontia, dysmorphic facies, and motor delay
• Spermatogenic failure 53
• Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis
• Visceral myopathy 2
• Vitreoretinopathy with phalangeal epiphyseal dysplasia

Modified diseases:

• Bleeding disorder, platelet-type 8 -> Bleeding disorder, platelet-type, 8
• Bleeding disorder, platelet-type 11 -> Bleeding disorder, platelet-type, 11
• Bleeding disorder, platelet-type 13 -> Bleeding disorder, platelet-type, 13
• Bleeding disorder, platelet-type 16 -> Bleeding disorder, platelet-type, 16
• Bleeding disorder, platelet-type 15 -> Bleeding disorder, platelet-type, 15
• Bleeding disorder, platelet-type 17 -> Bleeding disorder, platelet-type, 17
• Bleeding disorder, platelet-type 18 -> Bleeding disorder, platelet-type, 18
• Bleeding disorder, platelet-type 19 -> Bleeding disorder, platelet-type, 19
• Bleeding disorder, platelet-type 20 -> Bleeding disorder, platelet-type, 20
• Bleeding disorder, platelet-type 21 -> Bleeding disorder, platelet-type, 21
• Bleeding disorder, platelet-type 22 -> Bleeding disorder, platelet-type, 22

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• 4-(1-hydroxyethyl)-7-isoleucino-2-(threonin-O3-ylcarbonyl)-7,8-dihydroquinolin-8-ol (Ile-Thr)

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• Phosphatidylserine amidated glycine

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 5-glutamyl glycine
• ADP-alpha-D-ribosylarginine

Headline

The importance of being disordered

Intrinsically disordered regions are protein regions that lack a fixed or ordered three-dimensional structure, typically in the absence of interaction partners. They are thought to often drive liquid-liquid phase separation within cells. This process leads to the formation of biomolecular condensates devoid of a surrounding lipid membrane, which are responsible for extensively compartmentalizing eukaryotic cells. Liquid-liquid phase separation plays crucial roles in fundamental cellular processes, such as the stress response, among others. Indeed eukaryotic cells react to a wide range of stresses by assembling proteins and mRNAs into massive ribonucleoprotein stress granules (SGs) that regulate mRNA translation and degradation. Interestingly mRNAs modified through the methylation of adenosine (m⁶A) are enriched in SGs. The m⁶A modification is very common, with around 25% of mRNAs containing at least one m⁶A. It is recognized by a protein domain, called YTH, which is conserved from yeast to humans. In humans and mice, there are 3 such proteins, YTHDF1, YTHDF2 and YTHDF3. All 3 paralogs contain a C-terminal YTH domain and disordered regions are predicted in their N-terminal moieties. These proteins colocalize with stress granules.

Could YTHDF proteins and their modified RNA partners be active players in the process of stress granule formation? In vitro, RNAs containing at least 4 copies of m⁶A motifs, but not those with a single motif, dramatically enhance phase separation of YTHDF proteins. When transfected into cells, multivalent m⁶A RNA oligos promote localization of YTHDF proteins to stress granules. Moreover, depletion of YTHDF proteins inhibits SG formation and recruitment of mRNAs to SGs. Both the N-terminal intrinsically disordered region and the C-terminal m⁶A-binding YTH domain of YTHDF proteins are required for SG formation. It has been proposed that polymethylated mRNAs may act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation.

As of this release, we have introduced predictions of long, intrinsically disordered regions into the UniProtKB annotation pipeline, using the MobiDB-lite method. YTHDF entries have been updated and are now publicly available.

UniProt knowledge graph news

Using UniProt in a public cloud is now easier than ever, as UniProt is now available as part of the AWS open data program. AWS has published a tutorial on how you can use the public UniProt data in your own private graph database using AWS Neptune. This shows how the I (for Interoperability) in FAIR UniProt works with commercial cloud-based tools. Of course the UniProt Knowledge Graph remains freely available at sparql.uniprot.org.

UniProtKB news

Introduction of MobiDB-lite predictions for intrinsically disordered regions

Starting with this release of UniProt, we import predictions of intrinsically disordered regions and regions of compositional bias, generated with the MobiDB-lite method, in UniProtKB/Swiss-Prot. These computationally generated annotations are represented as Region and Compositional bias annotations tagged with the evidence code ECO:0000256 (sequence model evidence used in automatic assertion) and source SAM:MobiDB-lite. Entries with disordered regions can be retrieved using these queries:

annotation:(type:region disordered) AND reviewed:yes
annotation:(type:compbias) AND reviewed:yes

In cases where there is experimental evidence for intrinsically disordered regions, curators can modify the predicted results, or add new expert-curated regions, using the appropriate experimental evidence attribution.

Predictions from the MobiDB-lite method are also available for protein sequences in UniProtKB/TrEMBL - tagged with the same evidence code and source as in reviewed entries. They can be obtained by using these queries:

annotation:(type:region disordered) AND reviewed:no
annotation:(type:compbias) AND reviewed:no

See also:

• SAM - Sequence Analysis Methods for automatic annotation

Changes to the controlled vocabulary of human diseases

New diseases:

• Albinism, oculocutaneous, 8
• AMED syndrome, digenic
• Amyotrophic lateral sclerosis 26, with or without frontotemporal dementia
• Blistering, acantholytic, of oral and laryngeal mucosa
• Carpal tunnel syndrome 2
• Chorioretinal atrophy, progressive bifocal
• Deafness, autosomal recessive, 117
• Deafness, congenital, and adult-onset progressive leukoencephalopathy
• Developmental and epileptic encephalopathy 90
• Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy
• ENDOVE syndrome, limb-brain type
• ENDOVE syndrome, limb-only type
• Epilepsy, progressive myoclonic 12
• Erythrokeratodermia variabilis et progressiva 7
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 5
• Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
• Gastric adenocarcinoma and proximal polyposis of the stomach
• Hermansky-Pudlak syndrome 11
• Immunodeficiency 76
• Intellectual developmental disorder, autosomal dominant 64
• Intellectual developmental disorder with paroxysmal dyskinesia or seizures
• Joubert syndrome 37
• Leber hereditary optic neuropathy modifier
• Lessel-Kreienkamp syndrome
• Leukoencephalopathy, progressive, infantile-onset, with or without deafness
• Li-Campeau syndrome
• Macroglobulinemia, Waldenstrom, 1
• Mental retardation, X-linked 50
• Microcephaly 26, primary, autosomal dominant
• Microcephaly 27, primary, autosomal dominant
• Mitochondrial complex I deficiency, nuclear type 36
• Mitochondrial complex II deficiency, nuclear type 2
• Mitochondrial complex II deficiency, nuclear type 3
• Mitochondrial complex II deficiency, nuclear type 4
• Multiple congenital anomalies-neurodevelopmental syndrome, X-linked
• Myopathy, myofibrillar, 11
• Nephrotic syndrome 22
• Nephrotic syndrome 23
• Neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities
• Neurodevelopmental disorder with or without early-onset generalized epilepsy
• Neurofacioskeletal syndrome with or without renal agenesis
• Neuropathy, hereditary motor, with myopathic features
• Oculomotor-abducens synkinesis
• Olmsted syndrome 2
• Oocyte maturation defect 10
• Premature ovarian failure 18
• Proteasome-associated autoinflammatory syndrome 4
• Proteasome-associated autoinflammatory syndrome 5
• Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
• Spermatogenic failure, X-linked, 3
• Spermatogenic failure 51
• Spermatogenic failure 52
• Sulfide:quinone oxidoreductase deficiency
• Vertebral, cardiac, tracheoesophageal, renal, and limb defects

Modified diseases:

• Amyotrophic lateral sclerosis 12 -> Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia
• Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia -> Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
• Birk-Barel mental retardation dysmorphism syndrome -> Birk-Barel syndrome
• COACH syndrome -> COACH syndrome 1
• Diabetes mellitus, permanent neonatal 1 -> Diabetes mellitus, permanent neonatal, 1
• Diabetes mellitus, permanent neonatal 2 -> Diabetes mellitus, permanent neonatal, 2
• Diabetes mellitus, permanent neonatal 3 -> Diabetes mellitus, permanent neonatal, 3
• Diabetes mellitus, permanent neonatal 4 -> Diabetes mellitus, permanent neonatal, 4
• Epileptic encephalopathy, early infantile, 57 -> Developmental and epileptic encephalopathy 57
• Epileptic encephalopathy, early infantile, 85, with or without midline brain defects -> Developmental and epileptic encephalopathy 85 with or without midline brain defects
• Frontotemporal dementia, chromosome 3-linked -> Frontotemporal dementia and/or amyotrophic lateral sclerosis 7
• Generalized thyroid hormone resistance -> Thyroid hormone resistance, generalized, autosomal dominant
• Generalized thyroid hormone resistance autosomal recessive -> Thyroid hormone resistance, generalized, autosomal recessive
• Hemophagocytic lymphohistiocytosis, familial, 6 -> Immune dysregulation and systemic hyperinflammation syndrome
• Intellectual developmental disorder 59 -> Intellectual developmental disorder, autosomal dominant 59
• Intellectual developmental disorder 60 with seizures -> Intellectual developmental disorder, autosomal dominant 60, with seizures
• Intellectual developmental disorder 61 -> Intellectual developmental disorder, autosomal dominant 61
• Intellectual developmental disorder 62 -> Intellectual developmental disorder, autosomal dominant 62
• Mental retardation, autosomal recessive 15 -> Rafiq syndrome
• Methylmalonic aciduria type mut -> Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
• Mitochondrial complex II deficiency -> Mitochondrial complex II deficiency, nuclear type 1
• Neurodevelopmental disorder with alopecia and brain abnormalities -> Bachmann-Bupp syndrome
• Vasculopathy, retinal, with cerebral leukodystrophy -> Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations

Deleted disease

• Amyotrophic lateral sclerosis 17

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-alpha-linked (Rha) arginine

Modified term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-linked (GlcNAc) arginine -> N-beta-linked (GlcNAc) arginine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Bacterial microcompartment
• Cytolytic granule
• Cytolytic granule lumen
• Cytolytic granule membrane
• Zymogen granule
• Zymogen granule lumen
• Zymogen granule membrane

Changes to keywords

New keyword:

• Bacterial microcompartment

Headline

With a little help from my friend

One of the early responses to eukaryotic DNA damage is ADP-ribosylation of histones and other proteins in the vicinity of the lesion. This post-translation modification, which is important for the decompaction of chromatin and the recruitment of repair factors, can be catalyzed by two related enzymes: PARP1 or PARP2. In the absence of binding partners, the PARPs catalyze ADP-ribosylation on aspartate or glutamate residues. However, in the context of DNA damage, ADP-ribosylation predominantly occurs on serine residues. The switch in amino acid specificity requires the presence of a protein cofactor HPF1. Its mechanism was unraveled recently through the study of the X-ray crystal structure of the PARP2-HPF1 complex.

Under resting, or low stress conditions, the interaction between PARP1 or PARP2 and HPF1 is limited by an inhibitory domain in PARP. In response to high and acute levels of DNA damage, PARP binds DNA and undergoes conformational changes, the inhibitory domain is unfolded, and the interaction with HPF1 is stabilized. Within the complex, PARP2 and HPF1 form a new joint active site with an HPF1 glutamate residue positioned at the very core of the enzyme. Mutagenesis of this glutamate residue to alanine does not affect HPF1 binding to PARP2, but does impair serine ADP-ribosylation. This glutamate within the active site is thought to allow the deprotonation of the serine residue, making it a favorable target for nucleophilic attack. This step is dispensable when the substrate is an aspartate or glutamate residue that is deprotonated at neutral pH. In addition to its active role in catalysis per se, HPF1 may also participate in substrate recognition. Indeed, a putative peptide-binding canyon may form at the interface of HPF1 and PARP2. This site seems perfectly suited for binding lysine-serine motifs that are highly enriched among serine-ADP-ribosylation substrates in vivo.

This discovery goes beyond the excitement of unraveling a new mechanism in a crucial process in DNA repair. It may also have an impact in a clinical setting. PARP small inhibitors have been approved for the treatment of BRCA-negative breast, ovarian and fallopian tube cancers, and it has been previously shown that human cells lacking HPF1 exhibit sensitivity to DNA damaging agents and PARP inhibition. Therefore it may be of interest to re-evaluate the potency and selectivity of existing PARP inhibitors in the presence of HPF1-PARP1/2 complexes and to develop new drugs that would specifically interfere with HPF1-mediated PARP1/2 activity, but not with PARP1/2 enzymatic activity on non-serine residues.

As of this release, HPF1, PARP1 and PARP2 entries have been updated and are publicly available.

UniProt website news

Visualization of subcellular location annotation using SwissBioPics

As of this release, we are using the SwissBioPics library of interactive biological images for the visualization of subcellular location data to enhance the representation of UniProt and Gene Ontology (GO) subcellular location annotations.

SwissBioPics covers cell types from all kingdoms of life - ranging from muscle, neuronal and epithelial cells of animals, to the rods, cocci, clubs, spirals and other more exotic forms of bacteria and archaea. A reusable web component and an API allow website developers to visualize subcellular location data (in the form of GO cellular component or UniProt subcellular location identifiers) on these images. The code and technical documentation are available at npmjs.com.

Examples:

• Magnetosome formation protease MamE from M.magneticum
• Spore membrane assembly protein 2 from S.cerevisiae
• Potassium voltage-gated channel subfamily D member 2 from H.sapiens

UniProtKB news

Change of evidence codes for combinatorial evidence

When UniProt adopted the Evidence Code Ontology (ECO) in 2014, we chose to use the concepts ECO:0000244 in manual assertions and ECO:0000213 in automatic assertions, respectively, for information inferred from a combination of experimental and computational evidence. These two ECO concepts have in fact a broader meaning that includes combinations of any type of evidence, and meanwhile the ECO has been extended with concepts that exactly reflect our usage. We have therefore replaced ECO:0000244 by ECO:0007744 and ECO:0000213 by ECO:0007829.

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis, distal, 1C
• Cardioacrofacial dysplasia 1
• Cardioacrofacial dysplasia 2
• Cardiofacioneurodevelopmental syndrome
• Cleft palate, proliferative retinopathy, and developmental delay
• COACH syndrome 2
• COACH syndrome 3
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1
• Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
• Combined oxidative phosphorylation deficiency 51
• Deafness, autosomal dominant, 78
• Deafness, autosomal dominant, 79
• Deafness, autosomal recessive, 116
• Delpire-McNeill syndrome
• Developmental and epileptic encephalopathy 89
• Focal segmental glomerulosclerosis 10
• Immunodeficiency 75
• Inflammatory bowel disease 30
• Intellectual developmental disorder with speech delay and axonal peripheral neuropathy
• Kaya-Barakat-Masson syndrome
• Kilquist syndrome
• Leukodystrophy, hypomyelinating, 20
• Mandibuloacral dysplasia progeroid syndrome
• Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1
• Mismatch repair cancer syndrome 2
• Mismatch repair cancer syndrome 3
• Mismatch repair cancer syndrome 4
• Mitochondrial complex IV deficiency, nuclear type 1
• Mitral valve prolapse 3
• Monosomy 7 myelodysplasia and leukemia syndrome 1
• Monosomy 7 myelodysplasia and leukemia syndrome 2
• Mucoepithelial dysplasia, hereditary
• Neurodevelopmental disorder with alopecia and brain abnormalities
• Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
• Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities
• Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities
• Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities
• Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy
• Neurodevelopmental disorder with seizures and brain atrophy
• Neurodevelopmental disorder with speech impairment and dysmorphic facies
• Neuronopathy, distal hereditary motor, 5C
• Nivelon-Nivelon-Mabille syndrome
• Noonan syndrome 13
• Osteogenesis imperfecta 21
• Premature ovarian failure 17
• Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome
• Ritscher-Schinzel syndrome 3
• Spermatogenic failure 45
• Spermatogenic failure 46
• Spermatogenic failure 47
• Spermatogenic failure 48
• Spermatogenic failure 49
• Spermatogenic failure 50
• Thrombocytopenia 7
• Vertebral hypersegmentation and orofacial anomalies
• VEXAS syndrome
• Vitamin D-dependent rickets 3

Modified diseases:

• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 -> Mitochondrial complex IV deficiency, nuclear type 2
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 -> Mitochondrial complex IV deficiency, nuclear type 6
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 -> Mitochondrial complex IV deficiency, nuclear type 9
• Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4 -> Mitochondrial complex IV deficiency, nuclear type 13
• Epileptic encephalopathy, early infantile, 1 -> Developmental and epileptic encephalopathy 1
• Epileptic encephalopathy, early infantile, 2 -> Developmental and epileptic encephalopathy 2
• Epileptic encephalopathy, early infantile, 3 -> Developmental and epileptic encephalopathy 3
• Epileptic encephalopathy, early infantile, 4 -> Developmental and epileptic encephalopathy 4
• Epileptic encephalopathy, early infantile, 5 -> Developmental and epileptic encephalopathy 5
• Epileptic encephalopathy, early infantile, 6 -> Dravet syndrome
• Epileptic encephalopathy, early infantile, 7 -> Developmental and epileptic encephalopathy 7
• Epileptic encephalopathy, early infantile, 8 -> Developmental and epileptic encephalopathy 8
• Epileptic encephalopathy, early infantile, 9 -> Developmental and epileptic encephalopathy 9
• Epileptic encephalopathy, early infantile, 11 -> Developmental and epileptic encephalopathy 11
• Epileptic encephalopathy, early infantile, 12 -> Developmental and epileptic encephalopathy 12
• Epileptic encephalopathy, early infantile, 13 -> Developmental and epileptic encephalopathy 13
• Epileptic encephalopathy, early infantile, 14 -> Developmental and epileptic encephalopathy 14
• Epileptic encephalopathy, early infantile, 15 -> Developmental and epileptic encephalopathy 15
• Epileptic encephalopathy, early infantile, 16 -> Developmental and epileptic encephalopathy 16
• Epileptic encephalopathy, early infantile, 17 -> Developmental and epileptic encephalopathy 17
• Epileptic encephalopathy, early infantile, 18 -> Developmental and epileptic encephalopathy 18
• Epileptic encephalopathy, early infantile, 19 -> Developmental and epileptic encephalopathy 19
• Epileptic encephalopathy, early infantile, 21 -> Developmental and epileptic encephalopathy 21
• Epileptic encephalopathy, early infantile, 23 -> Developmental and epileptic encephalopathy 23
• Epileptic encephalopathy, early infantile, 24 -> Developmental and epileptic encephalopathy 24
• Epileptic encephalopathy, early infantile, 25, with amelogenesis imperfecta -> Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta
• Epileptic encephalopathy, early infantile, 26 -> Developmental and epileptic encephalopathy 26
• Epileptic encephalopathy, early infantile, 27 -> Developmental and epileptic encephalopathy 27
• Epileptic encephalopathy, early infantile, 28 -> Developmental and epileptic encephalopathy 28
• Epileptic encephalopathy, early infantile, 29 -> Developmental and epileptic encephalopathy 29
• Epileptic encephalopathy, early infantile, 30 -> Developmental and epileptic encephalopathy 30
• Epileptic encephalopathy, early infantile, 31 -> Developmental and epileptic encephalopathy 31
• Epileptic encephalopathy, early infantile, 32 -> Developmental and epileptic encephalopathy 32
• Epileptic encephalopathy, early infantile, 33 -> Developmental and epileptic encephalopathy 33
• Epileptic encephalopathy, early infantile, 34 -> Developmental and epileptic encephalopathy 34
• Epileptic encephalopathy, early infantile, 35 -> Developmental and epileptic encephalopathy 35
• Epileptic encephalopathy, early infantile, 36 -> Developmental and epileptic encephalopathy 36
• Epileptic encephalopathy, early infantile, 37 -> Developmental and epileptic encephalopathy 37
• Epileptic encephalopathy, early infantile, 38 -> Developmental and epileptic encephalopathy 38
• Epileptic encephalopathy, early infantile, 39 -> Developmental and epileptic encephalopathy 39
• Epileptic encephalopathy, early infantile, 40 -> Developmental and epileptic encephalopathy 40
• Epileptic encephalopathy, early infantile, 41 -> Developmental and epileptic encephalopathy 41
• Epileptic encephalopathy, early infantile, 42 -> Developmental and epileptic encephalopathy 42
• Epileptic encephalopathy, early infantile, 43 -> Developmental and epileptic encephalopathy 43
• Epileptic encephalopathy, early infantile, 44 -> Developmental and epileptic encephalopathy 44
• Epileptic encephalopathy, early infantile, 45 -> Developmental and epileptic encephalopathy 45
• Epileptic encephalopathy, early infantile, 46 -> Developmental and epileptic encephalopathy 46
• Epileptic encephalopathy, early infantile, 47 -> Developmental and epileptic encephalopathy 47
• Epileptic encephalopathy, early infantile, 48 -> Developmental and epileptic encephalopathy 48
• Epileptic encephalopathy, early infantile, 49 -> Developmental and epileptic encephalopathy 49
• Epileptic encephalopathy, early infantile, 50 -> evelopmental and epileptic encephalopathy 50
• Epileptic encephalopathy, early infantile, 51 -> Developmental and epileptic encephalopathy 51
• Epileptic encephalopathy, early infantile, 52 -> Developmental and epileptic encephalopathy 52
• Epileptic encephalopathy, early infantile, 53 -> Developmental and epileptic encephalopathy 53
• Epileptic encephalopathy, early infantile, 54 -> Developmental and epileptic encephalopathy 54
• Epileptic encephalopathy, early infantile, 55 -> Developmental and epileptic encephalopathy 55
• Epileptic encephalopathy, early infantile, 56 -> Developmental and epileptic encephalopathy 56
• Epileptic encephalopathy, early infantile, 58 -> Developmental and epileptic encephalopathy 58
• Epileptic encephalopathy, early infantile, 59 -> Developmental and epileptic encephalopathy 59
• Epileptic encephalopathy, early infantile, 60 -> Developmental and epileptic encephalopathy 60
• Epileptic encephalopathy, early infantile, 61 -> Developmental and epileptic encephalopathy 61
• Epileptic encephalopathy, early infantile, 62 -> Developmental and epileptic encephalopathy 62
• Epileptic encephalopathy, early infantile, 63 -> Developmental and epileptic encephalopathy 63
• Epileptic encephalopathy, early infantile, 64 -> Developmental and epileptic encephalopathy 64
• Epileptic encephalopathy, early infantile, 65 -> Developmental and epileptic encephalopathy 65
• Epileptic encephalopathy, early infantile, 66 -> Developmental and epileptic encephalopathy 66
• Epileptic encephalopathy, early infantile, 67 -> Developmental and epileptic encephalopathy 67
• Epileptic encephalopathy, early infantile, 68 -> Developmental and epileptic encephalopathy 68
• Epileptic encephalopathy, early infantile, 69 -> Developmental and epileptic encephalopathy 69
• Epileptic encephalopathy, early infantile, 70 -> Developmental and epileptic encephalopathy 70
• Epileptic encephalopathy, early infantile, 71 -> Developmental and epileptic encephalopathy 71
• Epileptic encephalopathy, early infantile, 72 -> Developmental and epileptic encephalopathy 72
• Epileptic encephalopathy, early infantile, 73 -> Developmental and epileptic encephalopathy 73
• Epileptic encephalopathy, early infantile, 74 -> Developmental and epileptic encephalopathy 74
• Epileptic encephalopathy, early infantile, 75 -> Developmental and epileptic encephalopathy 75
• Epileptic encephalopathy, early infantile, 76 -> Developmental and epileptic encephalopathy 76
• Epileptic encephalopathy, early infantile, 78 -> Developmental and epileptic encephalopathy 78
• Epileptic encephalopathy, early infantile, 79 -> Developmental and epileptic encephalopathy 79
• Epileptic encephalopathy, early infantile, 80 -> Developmental and epileptic encephalopathy 80
• Epileptic encephalopathy, early infantile, 81 -> Developmental and epileptic encephalopathy 81
• Epileptic encephalopathy, early infantile, 82 -> Developmental and epileptic encephalopathy 82
• Epileptic encephalopathy, early infantile, 83 -> Developmental and epileptic encephalopathy 83
• Epileptic encephalopathy, early infantile, 84 -> Developmental and epileptic encephalopathy 84
• Epileptic encephalopathy, early infantile, 86 -> Developmental and epileptic encephalopathy 86
• Epileptic encephalopathy, early infantile, 87 -> Developmental and epileptic encephalopathy 87
• Epileptic encephalopathy, early infantile, 88 -> Developmental and epileptic encephalopathy 88
• Leigh syndrome French-Canadian type -> Mitochondrial complex IV deficiency, nuclear type 5

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• O-di-AMP-tyrosine
• O-tri-AMP-tyrosine
• 5-glutamyl dopamine
• 5-glutamyl noradrenaline
• 5-glutamyl serotonin

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• L-isoglutamyl histamine -> 5-glutamyl histamine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Cortical granule
• Dynein axonemal particle
• Spore
• Zona pellucida

Modified subcellular location:

• Postsynaptic Golgi apparatus -> Golgi outpost
• Spore core membrane -> Spore membrane

(Almost) all about that CBASS

Bacteria and archaea, like every other living organisms, must defend themselves against viral (bacteriophage or phage) attack. It is estimated that there are 10³¹ bacteriophages on the planet found in all habitats; sea water, animal gastrointestinal tracts, oceanic basement... A number of anti-phage defense mechanisms are known: restriction nucleases, an Argonaute-like system, CRISPR, and more are being discovered as we explore less well-known archaea and bacteria. A new phage defense mechanism has been recently discovered and is being characterized, the CBASS system (Cyclic oligonucleotide-Based Anti-phage Signalling System).

At the heart of each CBASS system is a cyclic nucleotide synthase. These belong to the cGAS/DncV-like nucleotidyltransferase family (abbreviated CD-NTase), and they make cyclic di-, tri-, and possibly even tetranucleotides. The cyclic nucleotides activate an effector protein, encoded adjacently to the CD-NTase. The effectors have a variety of activities: nucleases that degrade all DNA, including viral DNA (NucC, Cap4), an NAD+ hydrolase that presumably depletes cellular NAD+ (Cap12), phospholipases that are capable of degrading the cell membrane (CapV, CapE), and transmembrane proteins that may form pores (Cap13) have all been observed, although not all have been characterized yet.

Transforming CBASS into bacteria without a natural CBASS system protects the population against phages. The effectors lead to cell death before the phage have completed an infection cycle, thus protecting adjacent uninfected cells from infection. There are at least 4 types of CBASS systems, classified on basis of the presence or absence of ancillary genes encoded in the same locus. Type I systems have no extra genes. In type II systems, the ancillary proteins Cap2 and Cap3 are not necessary for protection against all phages, but they enlarge the range of phages against which the system is active. In type III systems, the ancillary proteins Cap6 and Cap7 control the activity of the system; Cap7 is required to activate the CD-NTase, while Cap6 prevents the Cap7-CD-NTase association. A subtype has a second Cap7-like gene called Cap8 which may act as a scaffold for complex assembly. Type IV systems are rare and so far uncharacterized. They occur mostly in Firmicutes and archaea.

At the request of Dr. Philip Kranzusch, the lead author on many of these papers, characterized CBASS proteins have been annotated. We'd like to thank Dr. Kranzusch, members of his lab, and Dr. R. Sorek for answering annotation questions. We also thank you for your interest in our knowledgebase and remind you that we are always looking for your input on our entries.

UniProtKB news

Change of the cross-references to EuPathDB: renamed to VEuPathDB

We have updated our cross-references to reflect the name change of EuPathDB into VEuPathDB, following the inclusion of genomes of invertebrate vectors of human pathogens.

Removal of the cross-references to VectorBase

Direct cross-references to VectorBase have been removed, as VectorBase is now part of the VEuPathDB resources.

Removal of the cross-references to UniCarbKB

Cross-references to UniCarbKB have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Autoinflammation, immune dysregulation, and eosinophilia
• Coenzyme Q10 deficiency, primary, 9
• Combined oxidative phosphorylation deficiency 48
• Combined oxidative phosphorylation deficiency 49
• Combined oxidative phosphorylation deficiency 50
• DEEAH syndrome
• Hemophagocytic lymphohistiocytosis, familial, 6
• Ichthyosis, lamellar, autosomal dominant
• IFAP syndrome 2
• Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia
• Immunodeficiency 73C with defective neutrophil chemotaxis and hypogammaglobulinemia
• Intellectual developmental disorder, X-linked, syndromic, Armfield type
• Intellectual developmental disorder with seizures and language delay
• Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies
• Mitochondrial complex I deficiency, nuclear type 35
• Mitochondrial complex IV deficiency, nuclear type 3
• Mitochondrial complex IV deficiency, nuclear type 4
• Mitochondrial complex IV deficiency, nuclear type 7
• Mitochondrial complex IV deficiency, nuclear type 8
• Mitochondrial complex IV deficiency, nuclear type 10
• Mitochondrial complex IV deficiency, nuclear type 11
• Mitochondrial complex IV deficiency, nuclear type 12
• Mitochondrial complex IV deficiency, nuclear type 14
• Mitochondrial complex IV deficiency, nuclear type 15
• Mitochondrial complex IV deficiency, nuclear type 16
• Mitochondrial complex IV deficiency, nuclear type 17
• Mitochondrial complex IV deficiency, nuclear type 18
• Mitochondrial complex IV deficiency, nuclear type 19
• Mitochondrial complex IV deficiency, nuclear type 20
• Mitochondrial complex IV deficiency, nuclear type 21
• Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B15
• Myopathy, epilepsy, and progressive cerebral atrophy
• Myopathy, myofibrillar, 10
• Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
• Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
• Oocyte maturation defect 8
• Oocyte maturation defect 9
• Optic atrophy 13 with retinal and foveal abnormalities
• Pallister-Hall-like syndrome
• Rajab interstitial lung disease with brain calcifications 2
• Retinitis pigmentosa 90
• Spastic paraplegia 83, autosomal recessive
• Spermatogenic failure 44
• Spinal muscular atrophy, infantile, James type
• Vissers-Bodmer syndrome

Modified diseases:

• Familial hemophagocytic lymphohistiocytosis 2 -> Hemophagocytic lymphohistiocytosis, familial, 2
• Familial hemophagocytic lymphohistiocytosis 3 -> Hemophagocytic lymphohistiocytosis, familial, 3
• Familial hemophagocytic lymphohistiocytosis 4 -> Hemophagocytic lymphohistiocytosis, familial, 4
• Familial hemophagocytic lymphohistiocytosis 5 -> Hemophagocytic lymphohistiocytosis, familial, 5
• Neutrophil immunodeficiency syndrome -> Immunodeficiency 73A with defective neutrophil chemotaxis and leukocytosis

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Autolysosome
• Autolysosome membrane
• Autolysosome lumen
• Ascus epiplasm

Changes to the humsavar.txt file and related keywords

The humsavar.txt file lists all missense variants annotated in UniProtKB/Swiss-Prot human entries. It provides a variant classification which is intended for research purposes only, not for clinical and diagnostic use. Variants were previously classified into the categories Disease, Polymorphisms and Unclassified. We have renamed these categories to follow the terminology recommended by the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) (Richards et al. PubMed:25741868):

Previous category	New category	Description
Disease	LP/P	likely pathogenic or pathogenic
Polymorphism	LB/B	likely benign or benign
Unclassified	US	uncertain significance

Previous format:

Main      Swiss-Prot             AA             Type of
gene name AC         FTId        change         variant       dbSNP          Disease name
_________ __________ ___________ ______________ _____________ ______________ _____________________
...
CC2D2A    Q9P2K1     VAR_075698  p.Trp1182Arg   Disease       rs386833755    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076881  p.Ser117Arg    Unclassified  rs186264635    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076882  p.Lys507Glu    Polymorphism  rs144439937    Joubert syndrome 9 (JBTS9) [MIM:612285]
...

New format:

Main      Swiss-Prot             AA             Variant
gene name AC         FTId        change         category dbSNP          Disease name
_________ __________ ___________ ______________ ________ ______________ _____________________
...
CC2D2A    Q9P2K1     VAR_075698  p.Trp1182Arg   LP/P     rs386833755    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076881  p.Ser117Arg    US       rs186264635    Joubert syndrome 9 (JBTS9) [MIM:612285]
CC2D2A    Q9P2K1     VAR_076882  p.Lys507Glu    LB/B     rs144439937    Joubert syndrome 9 (JBTS9) [MIM:612285]
...

Also in line with the ACMG/AMP guidelines, we have at the same time deprecated the keyword "Polymorphism" and renamed the keyword "Disease mutation" to "Disease variant". This was done because the terms 'polymorphism' and 'mutation', which have been widely used, often lead to confusion due to incorrect assumptions of pathogenic and benign effects, respectively.

Entries with variant annotations can be retrieved on the UniProt website with the query annotation:(type:variant).

UniProt FTP and website news

Changes to the FTP repository for reference proteomes

We currently distribute the UniProt reference proteomes on our FTP site in four taxonomic division folders (Archaea, Bacteria, Eukaryota and Viruses) and provide, for each proteome, its sequences in FASTA format and mappings from UniProt identifiers and gene names to those found in other databases. Starting from this release, we also publish the full protein records for a proteome in the UniProtKB text and XML format, and we have at the same time introduced a subfolder for each proteome that groups all its files in order to reduce the number of files in the taxonomic division folders.

Example: UP000005640

Previous FTP folder and files:

https://ftp.uniprot.org/pub/databases/uniprot/current_release/knowledgebase/reference_proteomes/Eukaryota/

• UP000005640_9606.fasta.gz
• UP000005640_9606_additional.fasta.gz
• UP000005640_9606_DNA.fasta.gz
• UP000005640_9606_DNA.miss.gz
• UP000005640_9606.idmapping.gz
• UP000005640_9606.gene2acc.gz

New FTP folder and files:

https://ftp.uniprot.org/pub/databases/uniprot/current_release/knowledgebase/reference_proteomes/Eukaryota/UP000005640/

• UP000005640_9606.dat.gz — UniProtKB text format
• UP000005640_9606.xml.gz — UniProtKB XML format
• UP000005640_9606.fasta.gz
• UP000005640_9606_additional.fasta.gz
• UP000005640_9606_DNA.fasta.gz
• UP000005640_9606_DNA.miss.gz
• UP000005640_9606.idmapping.gz
• UP000005640_9606.gene2acc.gz

Browser support change: End of support for Microsoft Internet Explorer

We have phased out support for Microsoft's Internet Explorer (IE 11), since our user base for this web browser is continuously decreasing and has significantly fallen below 1.5%. Please switch to a more recent and supported browser in order to enjoy the full functionalities of the UniProt website.

Even if you are not using IE 11, it may be a good idea to look at the list of the browsers we support and consider switching to the most recent version of your browser for the best user experience and security.

Headline

Venoms, gold mines for new antiprotozoal drugs

Neglected diseases are typically tropical infections, which are common in low-income populations in developing regions of Africa, Asia, and the Americas and affect more than one billion people. Among them, Chagas disease, also known as American trypanosomiasis, affects an estimated 6 to 7 million people worldwide. This disease is caused by the parasitic protozoan Trypanosoma cruzi. The disease is typically transmitted to humans and other mammals by the bite of infected triatomine insects, also known as kissing bugs or vampire bugs. Once inside the host, the protozoan invades cells near the site of inoculation, where it differentiates into an intracellular parasitic form called the amastigote. Amastigotes multiply, differentiate into trypomastigotes which burst the host cell, and are released into the circulation, from where they can invade a variety of tissues and repeat the same infectious cycle in new sites. In the early stage of infection, symptoms are mild, if any, and may include fever, swollen lymph nodes, headaches, or swelling at the site of the bite. After a few weeks, untreated individuals enter the chronic phase of disease and most do not show any further symptoms. However, in the long term (10-30 years after the initial illness), chronic infection may lead to cardiomyopathies, digestive tract pathologies, and up to 10% of people experience nerve damage.

There are only two drugs currently used to treat Chagas disease, benznidazole and nifurtimox. Unfortunately they are rarely beneficial during the chronic phase of the disease and can cause severe adverse effects. Moreover, resistance to these drugs is emerging in various parasitic strains. In this context, the observation that crude venom from a Brazilian ant called Dinoponera quadriceps had antichagasic activity and low toxicity in vitro offers one hope for the development of alternative therapies for Chagas disease. A venom component bearing this activity was identified as a 23-amino acid long peptide, called M-poneratoxin-Dq3a (M-PONTX-Dq3a). This peptide induced trypanosome necrosis and acted on the three parasitic forms: epimastigote (found in the gut of the vector insect), infectious trypomastigote and intracellular amastigote, suggesting that M-PONTX-Dq3a could be beneficial during the chronic phase of the infection. These effects were observed at concentrations low enough to avoid any toxicity for mammalian host cells contrary to benznidazole.

Ants are not the only organisms that can give us a hand in the fight against T. cruzi. Snakes, such as Bothrops atrox and Crotalus durissus terrificus, and wasps, such as Polybia paulista, have also been shown to produce antichagasic toxins. All venom toxins characterized so far were active against the three T. cruzi forms at concentrations that did not harm host cells. Their modes of action could differ, but all exhibited a high selectivity index (a ratio that measures the window between cytotoxicity and antimicrobial activity), which clearly qualifies them for further study in the development of new drugs.

Animal toxins with antichagasic properties have been manually annotated in UniProtKB/Swiss-Prot and are publicly available as of this release.

UniProtKB news

Removal of the cross-references to KO

Cross-references to KO (KEGG Orthology) have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis multiplex congenita 5
• Combined oxidative phosphorylation deficiency 45
• Combined oxidative phosphorylation deficiency 46
• Combined oxidative phosphorylation deficiency 47
• Cone-rod synaptic disorder syndrome, congenital non-progressive
• Epileptic encephalopathy, early infantile, 88
• Episodic ataxia 9
• Granulomatous disease, chronic, autosomal recessive, 5
• Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
• Heterotaxy, visceral, 9, autosomal, with male infertility
• Hyper-IgE recurrent infection syndrome 5, autosomal recessive
• Immunodeficiency 69
• Immunodeficiency 70
• Immunodeficiency 72 with autoinflammation
• Immunodeficiency 74, COVID19-related, X-linked
• Li-Ghorbani-Weisz-Hubshman syndrome
• Mitchell syndrome
• Mitochondrial DNA depletion syndrome 19
• Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies
• Neurodegeneration, infantile-onset, biotin-responsive
• Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities
• Oculopharyngodistal myopathy 2
• Optic atrophy 12
• Periodic fever, immunodeficiency, and thrombocytopenia syndrome
• Retinitis pigmentosa 32
• Retinitis pigmentosa 89
• Spondylometaphyseal dysplasia with corneal dystrophy
• Suleiman-El-Hattab syndrome
• Tolchin-Le Caignec syndrome
• Treacher Collins syndrome 4
• Warfarin sensitivity, X-linked

Modified diseases:

• Arthrogryposis multiplex congenita, neurogenic, with agenesis of the corpus callosum -> Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum
• Deafness, autosomal dominant, 1 -> Deafness, autosomal dominant 1, with or without thrombocytopenia
• Neuromuscular disease and ocular or auditory anomalies with or without seizures -> Neuromuscular oculoauditory syndrome
• Short stature, brachydactyly, intellectual developmental disability, and seizures -> Short stature, brachydactyly, impaired intellectual developmental, and seizures

Headline

PCK1 vacillating between gluconeogenesis and lipogenesis

Lipid metabolism is a tightly regulated process, which relies on sterol regulatory element-binding (SREBPs) transcription factors for the activation of genes involved in the synthesis of fatty acids, triglycerides, and cholesterol. In resting conditions, when the levels of cholesterol are sufficient, SREBPs are present as precursors in the endoplasmic reticulum (ER) membrane in complex with a protein called SCAP. SCAP also interacts with a member of the ER resident INSIG protein family. The interaction with INSIG ensures that the SCAP-SREBP complex is retained in the ER. When cholesterol levels drop, INSIG and SCAP no longer bind and the SCAP-SREBP complex is transported to the Golgi apparatus, where SREBP is cleaved and its cytosolic N-terminal transcription factor domain is freed to translocate to the nucleus and activate transcription.

There are cells, however, that do not bother about regulation and just desperately need lipogenesis to proliferate. These are cancer cells. How do they achieve the synthesis of enough lipids in normal sterol levels, in conditions in which lipogenesis would normally be inhibited? The answer came from a study in hepatocellular carcinoma (HCC) cell lines. In these cells, activation with IGF1, a stimulus critical for HCC development, leads to a cascade of phosphorylation, which starts with AKT1. Activated AKT1 in turn phosphorylates PCK1, which is then translocated from the cytosol to the ER and phosphorylates INSIG. This impairs INSIG binding to the SCAP-SREBP complex, resulting in the release of the complex from the ER to the Golgi apparatus, with subsequent SERBP activation.

The discovery of PCK1 involvement in this process comes as a surprise. PCK1 is not known to be involved in lipogenesis regulation, nor to have a kinase activity. It is a rate-limiting enzyme of gluconeogenesis, a pathway that generates glucose from certain non-carbohydrate carbon substrates. In this pathway, it converts oxaloacetate into phosphoenolpyruvate. PCK1 phosphorylation by AKT1 uncovers its cryptic kinase activity and redirects it to a completely different process. Cancer cells favor glycolysis to provide energy and metabolic intermediates, and suppress gluconeogenesis. For these cells, PCK1 diversion is necessary for cell growth, as expression of a PCK1 nonphosphorylatable mutant inhibits cell proliferation, and is costless, as inhibition of gluconeogenesis is not deleterious. Although the results have been produced in HCC cells, this process may also play a role in other cancer types. Indeed, AKT1 activation has been shown in melanoma, glioblastoma and non-small cell lung carcinoma cells.

PCK1-induced activation of SREBP1 may also occur in normal hepatocytes. In mice that were refed with glucose after 24 hours of fasting, phosphorylation of AKT1, PCK1, and INSIG proteins, as well as cleavage of SREBP1, were markedly enhanced in normal liver. These observations suggest that in vivo blood glucose levels may regulate the PCK1-mediated phosphorylation of INSIG proteins and the activation of SREBP. This might point toward a potential mechanism underlying overnutrition-promoted nonalcoholic fatty liver diseases.

As of this release, proteins involved in this new regulatory pathway have been updated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to CPTC

Cross-references have been added to CPTC, the CPTAC Antibody Portal. This portal serves as a National Cancer Institute (NCI) community resource that provides access to a large number of standardized renewable affinity reagents (to cancer-associated targets) and accompanying characterization data.

CPTC is available at https://proteomics.cancer.gov/antibody-portal.

The format of the explicit links is:

Resource abbreviation	CPTC
Resource identifier	UniProtKB accession number
Optional information 1	Number of antibodies

Example: P31751

Show all entries having a cross-reference to CPTC.

Text format

Example: P31751

DR   CPTC; P31751; 6 antibodies.

XML format

Example: P31751

<dbReference type="CPTC" id="P31751">
  <property type="antibodies" value="6 antibodies"/>
</dbReference>

RDF format

Example: P31751

uniprot:P31751
  rdfs:seeAlso <http://purl.uniprot.org/cptc/P31751> .
<http://purl.uniprot.org/cptc/P31751>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/CPTC> ;
  rdfs:comment "6 antibodies" .

Cross-references to BMRB

Cross-references have been added to the BMRB database, the Biological Magnetic Resonance Data Bank. BMRB collects, annotates, archives, and disseminates spectral and quantitative data derived from NMR spectroscopic investigations of biological macromolecules and metabolites.

BMRB is available at https://bmrb.io/.

The format of the explicit links is:

Resource abbreviation	BMRB
Resource identifier	UniProtKB accession number

Example: A1D240

Show all entries having a cross-reference to BMRB.

Text format

Example: A1D240

DR   BMRB; A1D240; -.

XML format

Example: A1D240

<dbReference type="BMRB" id="A1D240"/>

RDF format

Example: A1D240

uniprot:A1D240
  rdfs:seeAlso <http://purl.uniprot.org/bmrb/A1D240> .
<http://purl.uniprot.org/bmrb/A1D240>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/BMRB> .

Cross-references to PCDDB

Cross-references have been added to the PCDDB database, the Protein Circular Dichroism Data Bank. PCDDB is a public repository that archives and freely distributes circular dichroism (CD) and synchrotron radiation CD spectral data and their associated experimental metadata.

PCDDB is available at https://pcddb.cryst.bbk.ac.uk/.

The format of the explicit links is:

Resource abbreviation	PCDDB
Resource identifier	UniProtKB accession number

Example: Q70Q12

Show all entries having a cross-reference to PCDDB.

Text format

Example: Q70Q12

DR   PCDDB; Q70Q12; -.

XML format

Example: Q70Q12

<dbReference type="PCDDB" id="Q70Q12"/>

RDF format

Example: Q70Q12

uniprot:Q70Q12
  rdfs:seeAlso <http://purl.uniprot.org/pcddb/Q70Q12> .
<http://purl.uniprot.org/pcddb/Q70Q12>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PCDDB> .

Cross-references to SASBDB

Cross-references have been added to the SASBDB database, the Small Angle Scattering Biological Data Bank. SASBDB is a fully searchable curated repository of freely accessible and downloadable experimental scattering data, which are deposited together with the relevant experimental conditions, sample details, derived models and their fits to the data.

SASBDB is available at https://www.sasbdb.org/.

The format of the explicit links is:

Resource abbreviation	SASBDB
Resource identifier	UniProtKB accession number

Example: Q15326

Show all entries having a cross-reference to SASBDB.

Text format

Example: Q15326

DR   SASBDB; Q15326; -.

XML format

Example: Q15326

<dbReference type="SASBDB" id="Q15326"/>

RDF format

Example: Q15326

uniprot:Q15326
  rdfs:seeAlso <http://purl.uniprot.org/sasbdb/Q15326> .
<http://purl.uniprot.org/sasbdb/Q15326>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/SASBDB> .

Changes to the controlled vocabulary of human diseases

New diseases:

• 46,XX sex reversal 5
• Agenesis of corpus callosum, cardiac, ocular, and genital syndrome
• Arrhythmogenic right ventricular dysplasia, familial, 14
• Autism 20
• Combined oxidative phosphorylation deficiency 44
• Congenital disorder of glycosylation 2T
• Deafness, autosomal dominant, 77
• Diabetes mellitus, permanent neonatal 2
• Diabetes mellitus, permanent neonatal 3
• Diabetes mellitus, permanent neonatal 4
• Epilepsy, progressive myoclonic 11
• Epileptic encephalopathy, early infantile, 86
• Epileptic encephalopathy, early infantile, 87
• Fanconi renotubular syndrome 1
• Fanconi renotubular syndrome 5
• Galactosemia 4
• Glaucoma, primary closed-angle
• Harderoporphyria
• Hao-Fountain syndrome
• Hypoparathyroidism, familial isolated, 2
• Imerslund-Grasbeck syndrome 2
• Intellectual developmental disorder with autistic features and language delay, with or without seizures
• Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
• Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome
• Liberfarb syndrome
• Lissencephaly 10
• Microcephaly, developmental delay, and brittle hair syndrome
• Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline
• Neurodevelopmental, jaw, eye, and digital syndrome
• Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity
• Neurodevelopmental disorder with hypotonia, microcephaly, and seizures
• Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures
• Neurodevelopmental disorder with language impairment and behavioral abnormalities
• Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities
• Nizon-Isidor syndrome
• Periventricular nodular heterotopia 9
• Proteinuria, chronic benign
• Pseudo-TORCH syndrome 3
• Pyrin-associated autoinflammatory disease
• Radioulnar synostosis, non-syndromic
• Seizures, early-onset, with neurodegeneration and brain calcification
• Silver-Russell syndrome 4
• Silver-Russell syndrome 5
• Skeletal dysplasia, mild, with joint laxity and advanced bone age
• Sorbitol dehydrogenase deficiency with peripheral neuropathy
• Tremor, hereditary essential 6

Modified diseases:

• Abnormal thyroid hormone metabolism -> Thyroid hormone metabolism, abnormal
• Autoinflammation, antibody deficiency, and immune dysregulation PLCG2-associated -> Autoinflammation, antibody deficiency, and immune dysregulation
• Cardiac valvular dysplasia X-linked -> Cardiac valvular dysplasia, X-linked
• Cataract 46, juvenile-onset -> Cataract 46, juvenile-onset, with or without arrhythmic cardiomyopathy
• Contractures, pterygia, and variable skeletal fusions syndrome 1A -> Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A
• Contractures, pterygia, and variable skeletal fusions syndrome 1B -> Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B
• Cornelia de Lange syndrome 3 -> Cornelia de Lange syndrome 3 with or without midline brain defects
• Cornelia de Lange syndrome 4 -> Cornelia de Lange syndrome 4 with or without midline brain defects
• Crisponi/Cold-induced sweating syndrome 3 -> Perching syndrome
• D-lactic aciduria -> D-lactic aciduria with gout
• Deafness, X-linked, 5 -> Deafness, X-linked, 5, with peripheral neuropathy
• Diabetes mellitus, permanent neonatal -> Diabetes mellitus, permanent neonatal 1
• Dyskinesia, seizures, and intellectual developmental disorder -> Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures
• Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy -> Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 1
• Epimerase-deficiency galactosemia -> Galactosemia 3
• Familial adenomatous polyposis -> Familial adenomatous polyposis 1
• Familial hibernian fever -> Periodic fever, familial, autosomal dominant
• Familial hypercholesterolemia -> Hypercholesterolemia, familial, 1
• Familial ligand-defective apolipoprotein B-100 -> Hypercholesterolemia, familial, 2
• Galactosemia -> Galactosemia 1
• Galactosemia II -> Galactosemia 2
• Glycosylphosphatidylinositol biosynthesis defect 21 -> Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis
• Glycosylphosphatidylinositol deficiency -> Glycosylphosphatidylinositol biosynthesis defect 1
• Growth restriction, severe, with distinctive facies -> Silver-Russell syndrome 3
• Hereditary desmoid disease -> Desmoid disease, hereditary
• High density lipoprotein deficiency 1 -> Tangier disease
• High density lipoprotein deficiency 2 -> Hypoalphalipoproteinemia, primary, 1
• Hypercholesterolemia, autosomal dominant, 3 -> Hypercholesterolemia, familial, 3
• Hypercholesterolemia, autosomal recessive -> Hypercholesterolemia, familial, 4
• Hypoparathyroidism, familial isolated -> Hypoparathyroidism, familial isolated, 1
• Immunodeficiency 57 -> Immunodeficiency 57 with autoinflammation
• Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold -> Jansen-de Vries syndrome
• IRAK4 deficiency -> Immunodeficiency 67
• Keratitis-ichthyosis-deafness syndrome -> Keratitis-ichthyosis-deafness syndrome, autosomal dominant
• Knuckle pads, leukonychia, and sensorineural deafness -> Bart-Pumphrey syndrome
• Lujan-Fryns syndrome -> Intellectual developmental disorder, X-linked, syndromic, Lujan-Fryns type
• Melorheostosis -> Melorheostosis, isolated
• Mental retardation, autosomal dominant 9 -> NESCAV syndrome
• Mental retardation, autosomal dominant 24 -> Vulto-van Silfout-de Vries syndrome
• Mental retardation, autosomal dominant 25 -> Xia-Gibbs syndrome
• Mental retardation, autosomal dominant 27 -> Coffin-Siris syndrome 9
• Mental retardation, autosomal dominant 32 -> Arboleda-Tham syndrome
• Mental retardation, autosomal dominant 44 -> Intellectual developmental disorder, autosomal dominant 44, with microcephaly
• Mental retardation, autosomal dominant 49 -> Clark-Baraitser syndrome
• Mental retardation, X-linked, syndromic, ZDHHC9-related -> Intellectual developmental disorder, X-linked, syndromic, Raymond type
• Mental retardation, X-linked 102 -> Intellectual developmental disorder, X-linked, syndromic, Snijders Blok type
• Microcephaly, seizures, spasticity, and brain calcifications -> Diencephalic-mesencephalic junction dysplasia syndrome 1
• MYD88 deficiency -> Immunodeficiency 68
• Myopathy, proximal, and ophthalmoplegia -> Myopathy, proximal, with ophthalmoplegia
• Nail disorder, non-syndromic congenital, 10 -> Nail disorder, non-syndromic congenital, 1
• Neurodevelopmental disorder, X-linked, with craniofacial abnormalities -> Mullegama-Klein-Martinez syndrome
• Neurodevelopmental disorder with macrocephaly and with or without seizures -> Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
• Neuropathy, hereditary motor and sensory, 6B -> Neuropathy, hereditary motor and sensory, 6B, with optic atrophy
• Recessive hereditary megaloblastic anemia 1 -> Imerslund-Grasbeck syndrome 1
• Robinow syndrome autosomal recessive -> Robinow syndrome, autosomal recessive 1
• Rothmund-Thomson syndrome -> Rothmund-Thomson syndrome 2
• Silver-Russell syndrome -> Silver-Russell syndrome 1
• Spastic paraplegia 30, autosomal recessive -> Spastic paraplegia 30
• Thrombotic thrombocytopenic purpura congenital -> Thrombotic thrombocytopenic purpura, hereditary

Deleted diseases

• Arthrogryposis, distal, 8
• Ectodermal dysplasia, anhidrotic, with immunodeficiency, osteopetrosis and lymphedema
• Immunodeficiency, NEMO-related, without anhidrotic ectodermal dysplasia
• Recurrent isolated invasive pneumococcal disease 1
• Recurrent isolated invasive pneumococcal disease 2

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• O-alpha-linked (GlcNAc) threonine
• O-linked (Glc) threonine

Changes to keywords

New keyword:

• Carboxysome

Headline

Inflammation: the Good, the Bad and the Ugly

In a world filled with (microbial) foes, inflammation is our best friend, helping us fight against invading microorganisms, promoting wound healing and tissue regeneration. When it gets out of hand, however, it becomes our worst enemy. For instance, inflammation is required for mice to fight Influenza virus A (IAV) infections, but animals challenged with high doses of virus experience elevated levels of inflammation, destruction of airway epithelia and eventually die, unless they are deficient in MLKL protein, an endogenous protein that induces cell death in response to orthomyxovirus infection.

The mechanism leading to this fatal issue has been recently elucidated. When IAV infects cells and replicates, newly formed IAV RNA duplexes can adopt the Z-confirmation. These very peculiar RNAs are recognized by ZBP1 protein as a pathogen-associated molecular pattern (PAMP) and initiate a cascade of reactions. Activated ZBP1 recruits RIPK3, which in turn can induce one of two forms of programmed cell death, apoptosis and pro-inflammatory necroptosis. In the presence of RIPK1, apoptosis is favored. In the absence of RIPK1, RIPK3 phosphorylates MLKL, which then induces necroptosis. Programmed cell death is an effective mechanism of IAV clearance that not only eliminates infected cells to limit virus spread but also serves to catalyze adaptive immune responses. When cell death is unrestrained, or when the mode of cell death is primarily necrotic, then injury and severe illness ensue, despite virus clearance.

The dark side of inflammation also includes chronic inflammatory diseases and although progress has been made in this field, the causes that initiate pathogenic inflammatory responses still remain elusive. Could ZBP1 be a player in this deadly game? In other words, can ZBP1 be activated in the absence of any viral infections? An answer to these questions came from a recent publication by Jiao et al.. The authors showed that endogenous retroelements (EREs) produce double-stranded RNAs (dsRNAs) adopting a Z-confirmation. These dsRNAs are recognized by ZBP1 and activate it. EREs derive either from ancient retroviral infections or from active retrotransposons and constitute over half of the human and mouse genomes. Most dsRNAs identified by Jiao et al. originate from B2 and Alu short interspersed nuclear elements, followed by long interspersed nuclear elements (specifically, L1 elements) and long terminal repeat elements. Hence, these old mates of ours may still be able to mimic viral infections. Indeed in RIPK1 knockout mice, deregulation of ERE expression may trigger ZBP1-dependent skin inflammation. This mechanism may be relevant for the pathogenesis of inflammatory pathologies in humans, particularly in patients with variations in proteins that inhibit the ZBP1-MLKL-induced necroptotic pathway, such as RIPK1.

As of this release, ZBP1, RIPK3, and MLKL have been updated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to GlyGen

Cross-references have been added to the GlyGen Computational and Informatics Resource for Glycoscience. GlyGen retrieves information from multiple international data sources, integrates and harmonizes this data and makes it searchable.

GlyGen is available at https://www.glygen.org.

The format of the explicit links is:

Resource abbreviation	GlyGen
Resource identifier	UniProtKB accession number
Optional information 1	Glycosylation details

Example: P07766

Show all entries having a cross-reference to GlyGen.

Text format

Example: P14210

DR   GlyGen; P14210; 5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site).

XML format

Example: P14210

<dbReference type="GlyGen" id="P14210">
  <property type="glycosylation" value="5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site)"/>
</dbReference>

RDF format

Example: P14210

uniprot:P07766
  rdfs:seeAlso <http://purl.uniprot.org/glygen/P14210> .
<http://purl.uniprot.org/glygen/P14210>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/GlyGen> ;
  rdfs:comment "5 sites, 8 N-linked glycans (4 sites), 1 O-linked glycan (1 site)" .

Cross-references to PathwayCommons

Cross-references have been added to the PathwayCommons, a resource that aims to collect and disseminate biological pathway and interaction data. Data is collected from partner databases and is represented in the BioPAX standard. By representing data in BioPAX, Pathway Commons is able to provide a detailed representation of a variety of biological concepts including: Biochemical reactions; gene regulatory networks; and genetic interactions; transport and catalysis events; and physical interactions involving proteins, DNA, RNA and small molecules and complexes.

PathwayCommons is available at http://www.pathwaycommons.org.

The format of the explicit links is:

Resource abbreviation	PathwayCommons
Resource identifier	UniProtKB accession number

Example: P01042

Show all entries having a cross-reference to PathwayCommons.

Text format

Example: P01042

DR   PathwayCommons; P01042; -.

XML format

Example: P01042

<dbReference type="PathwayCommons" id="P01042"/>

RDF format

Example: P01042

uniprot:P01042
  rdfs:seeAlso <http://purl.uniprot.org/pathwaycommons/P01042> .
<http://purl.uniprot.org/pathwaycommons/P01042>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PathwayCommons> .

Change to the cross-references to GlyConnect

We have introduced an additional field in the cross-references to the GlyConnect protein glycosylation database, a platform integrating sources of information to help characterize the molecular components of protein glycosylation. This allows us to provide some additional information, e.g. about the nature of the glycans and the number of glycosylation sites.

The format of the explicit links is:

Resource abbreviation	GlyConnect
Resource identifier	Resource identifier
Optional information 1	Glycosylation details

Text format

Example: P12763

Previous format:

DR   GlyConnect; 22; -.

New format:

DR   GlyConnect; 22; 49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites).

XML format

Example: P12763

Previous format:

<dbReference type="GlyConnect" id="22"/>

New format:

<dbReference type="GlyConnect" id="22">
  <property type="glycosylation" value="49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites)"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: P12763

Previous format

uniprot:P12763
  rdfs:seeAlso <http://purl.uniprot.org/glyconnect/22> .
<http://purl.uniprot.org/glyconnect/22>
  rdf:type <http://purl.uniprot.org/core/Resource> ;
  <http://purl.uniprot.org/core/database> <http://purl.uniprot.org/database/GlyConnect> .

New format:

uniprot:P12763
  rdfs:seeAlso <http://purl.uniprot.org/glyconnect/22> .
<http://purl.uniprot.org/glyconnect/22>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/GlyConnect> ;
  rdfs:comment "49 N-Linked glycans (3 sites), 13 O-Linked glycans (6 sites)" .

New automatic annotation system ARBA (Association-Rule-Based Annotator)

In the UniProt Automatic Annotation pipeline which enhances unreviewed (UniProtKB/TrEMBL) records by enriching them with automatic classification and annotation, the SAAS (Statistical Automatic Annotation System) component has been superseded by the more powerful ARBA (Association-Rule-Based Annotator). ARBA is a multiclass learning system trained on expertly annotated entries in UniProtKB/Swiss-Prot. ARBA uses rule mining techniques to generate concise annotation models with the highest representativeness and coverage for annotation, based on the properties of InterPro group membership and taxonomy. ARBA employs a data exclusion set that censors data not suitable for computational annotation (such as specific biophysical or chemical properties) and generates human-readable rules for each release. ARBA rules can be browsed and searched via the website.

Changes to the controlled vocabulary of human diseases

New diseases:

• 46,XY sex reversal 11
• Al-Gazali syndrome
• Alopecia-mental retardation syndrome 4
• Anauxetic dysplasia 3
• Autoinflammation with episodic fever and lymphadenopathy
• Bone marrow failure syndrome 6
• Combined oxidative phosphorylation deficiency 40
• Combined oxidative phosphorylation deficiency 41
• Combined oxidative phosphorylation deficiency 42
• Combined oxidative phosphorylation deficiency 43
• Cone-rod dystrophy 14
• Congenital disorder of glycosylation 2R
• Diets-Jongmans syndrome
• Epilepsy, early-onset, with or without developmental delay
• Epileptic encephalopathy, early infantile, 85, with or without midline brain defects
• Genitourinary and/or brain malformation syndrome
• Holoprosencephaly 13, X-linked
• Hypervalinemia and hyperleucine-isoleucinemia
• Hypogonadotropic hypogonadism 25 with anosmia
• Immunodeficiency 66
• Intellectual developmental disorder with poor growth and with or without seizures or ataxia
• Mitochondrial DNA depletion syndrome 18
• Muscular dystrophy, limb-girdle, autosomal recessive 26
• Myopathy, congenital, with respiratory insufficiency and bone fractures
• Myopathy, congenital proximal, with minicore lesions
• Nabais Sa-de Vries syndrome 1
• Nabais Sa-de Vries syndrome 2
• Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
• Respiratory papillomatosis, juvenile recurrent, congenital
• Retinal dystrophy with leukodystrophy
• Rhizomelic limb shortening with dysmorphic features
• Sandestig-Stefanova syndrome
• Spinocerebellar ataxia, autosomal recessive, 28
• T-cell immunodeficiency with thymic aplasia
• T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant
• Triokinase and FMN cyclase deficiency syndrome
• Vertebral, cardiac, renal, and limb defects syndrome 3
• Wieacker-Wolff syndrome, female-restricted

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• Isoaspartyl glycine isopeptide (Gly-Asp)

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 2-oxo-5,5-dimethylhexanoate
• 3-methylisoleucine
• 3-methylvaline
• 3-methyl-D-valine
• N4-methyl-D-asparagine
• 3-hydroxyvaline (Thr)
• (3S)-3-methylglutamine
• 3-hydroxy-D-valine
• (3R)-N4-methyl-3-hydroxy-D-asparagine
• 3,3-dimethylmethionine
• Diphosphoserine
• Diphosphothreonine

Modified terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Lactic acid -> D-lactate
• 3-hydroxyvaline -> 3-hydroxyvaline (Val)

Headline

Mitochondrial call for help

Life is a continuous chain of issues that have to be addressed for survival and our cells know all about that. Hypoxia, amino acid deprivation, glucose deprivation, viral infection, endoplasmic reticulum stress are but a few examples. That's why eukaryotic cells have developed an elaborate signaling pathway, called the integrated stress response (ISR), which is activated in the cytosol in response to a range of physiological changes and pathological conditions. Stress stimuli that activate ISR all converge on the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (EIF2A). Depending upon the stress stimulus, the reaction is catalyzed by one of the four following kinases: GCN2/EIF2AK4, PERK/EIF2AK3, PKR/EIF2AK2 and HRI/EIF2AK1. EIF2A phosphorylation leads to attenuation in 5' cap-dependent protein synthesis, while promoting the translation of selected mRNAs that harbor a short upstream open reading frame in their 5'-untranslated region, including those for transcription factors ATF4, ATF5 or DDIT3 (also known as CHOP). ISR is primarily a survival program, but exposure to severe stress can also lead to apoptosis.

Mitochondrial stress also strongly induces the expression of ATF4 and DDIT3, and hence triggers ISR, but the pathway signaling mitochondrial stress to the cytosol was elusive until the publication of two articles in March of this year. DDIT3 induction requires at least two mitochondrial proteins: OMA1 and DELE1, and the cytosolic kinase HRI. OMA1 is a metalloprotease located in the mitochondrial inner membrane. It is activated by mitochondrial dysfunction, possibly via membrane depolarization. OMA1 cleaves DELE1 in the intermembrane space and the N-terminally truncated DELE1 fragment enters the cytosol where it interacts with and activates HRI and hence stress response. The consequences of ISR during mitochondrial dysfunction are not yet fully understood and DELE1 may not be the only mitochondrial ISR activator, but one missing link between mitochondrial stress and ISR has been clearly established.

As of this release, the OMA1 protease and DELE1 have been updated and are available in UniProtKB/Swiss-Prot. To annotate DELE1, we took advantage of the new format announced last December, which allows us to describe product-specific features, be it that of an alternative splicing isoform, for example, or of a peptide resulting from proteolytic cleavage. EIF2AK1 activation is a function restricted to the DELE1 cleavage product, and this uniqueness is clearly reported in the 'FUNCTION' subsection dedicated to DELE1 short form.

UniProtKB news

Cross-references to IDEAL

Cross-references have been added to the IDEAL database, a database of Intrinsically Disordered proteins.

IDEAL is available at http://idp1.force.cs.is.nagoya-u.ac.jp/IDEAL/.

The format of the explicit links is:

Resource abbreviation	IDEAL
Resource identifier	Resource identifier

Example: O15162

Show all entries having a cross-reference to IDEAL.

Text format

Example: O15162

DR   IDEAL; IID00006; -.

XML format

Example: O15162

<dbReference type="IDEAL" id="IID00006"/>

RDF format

Example: O15162

uniprot:O15162
  rdfs:seeAlso <http://identifiers.org/ideal/IID00006> .
<http://identifiers.org/ideal/IID00006>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/IDEAL> .

Cross-references to BioGRID-ORCS

Cross-references have been added to the BioGRID-ORCS database, a database of CRISPR phenotype screens.

BioGRID-ORCS is available at https://orcs.thebiogrid.org.

The format of the explicit links is:

Resource abbreviation	BioGRID-ORCS
Resource identifier	Resource identifier
Optional information 1	Number of hits

Example: Q96A29

Show all entries having a cross-reference to BioGRID-ORCS.

Text format

Example: Q96A29

DR   BioGRID-ORCS; 55343; 19 Hits in 787 CRISPR Screens.

XML format

Example: Q96A29

<dbReference type="BioGRID-ORCS" id="55343">
  <property type="hits" value="19 Hits in 787 CRISPR Screens"/>
</dbReference>

RDF format

Example: Q96A29

uniprot:Q96A29
  rdfs:seeAlso <http://purl.uniprot.org/biogrid-orcs/55343> .
<http://purl.uniprot.org/biogrid-orcs/55343>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/BioGRID-ORCS> ;
  rdfs:comment "19 Hits in 787 CRISPR Screens" .

Change to the cross-references to ABCD

We have introduced an additional field in the cross-references to the ABCD (AntiBodies Chemically Defined) database, a manually curated depository of sequenced antibodies. This allows us to specify the number of sequenced antibodies available for a given protein in UniProtKB.

Text format

Example: O75084

Previous format:

DR   ABCD; O75084; -.

New format:

DR   ABCD; O75084; 10 sequenced antibodies.

XML format

Example: O75084

Previous format:

<dbReference type="ABCD" id="O75084"/>

New format:

<dbReference type="ABCD" id="O75084"/>
  <property type="antibodies" value="10 sequenced antibodies"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: O75084

Previous format:

uniprot:O75084
  rdfs:seeAlso <http://purl.uniprot.org/abcd/O75084> .
<http://purl.uniprot.org/abcd/O75084>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/ABCD> .

New format:

uniprot:O75084
  rdfs:seeAlso <http://purl.uniprot.org/abcd/O75084> .
<http://purl.uniprot.org/abcd/O75084>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/ABCD> ;
  rdfs:comment "10 sequenced antibodies" .

Change of the cross-references to MycoCLAP

The MycoCLAP resource has changed its name to CLAE and we have updated our cross-references to reflect this name change.

Cross-references to BioGRID

The BioGrid database was renamed BioGRID. We changed the database name in the relevant cross-references (DR lines in the flat file) accordingly.

Example:

DR   BioGRID; 198188; 12.

Cross-references to Unimod in the ptmlist.txt document file

The ptmlist.txt document, which is available by FTP and on the website, describes post-translational modifications (PTMs) annotated in the UniProt knowledgebase. This release sees the addition of optional cross-references from ptmlist.txt to Unimod, an open access database of protein modifications for use in mass spectrometry applications which provides molecular-level details of PTMs (both natural and non-natural) including molecular formula, target residues, monoisotopic and average mass shifts and literature references with a community-driven curation.

Example:

ID   (3R)-3-hydroxyasparagine
AC   PTM-0369
FT   MOD_RES
..
KW   Hydroxylation.
..
DR   Unimod; 35.

This new mapping to Unimod will facilitate the integration of data on PTMs identified by mass spectrometry based proteomics.

We have currently mapped 236 of the most common PTMs in UniProtKB to Unimod and will continue to add new cross-references to Unimod in forthcoming releases. This mapping of PTMs to Unimod is part of our ongoing work on the standardization of knowledge of PTMs in UniProtKB by providing cross-references to a resource which is widely used in proteomics bioinformatics. We welcome your feedback on these current and future developments.

Changes to the controlled vocabulary of human diseases

New diseases:

• Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome
• Aneurysm, intracranial berry, 12
• Arthrogryposis multiplex congenita, neurogenic, with agenesis of the corpus callosum
• Basal ganglia calcification, idiopathic, 8, autosomal recessive
• Beck-Fahrner syndrome
• Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT
• CATIFA syndrome
• CEBALID syndrome
• Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay
• Ciliary dyskinesia, primary, 44
• Ciliary dyskinesia, primary, 45
• Coffin-Siris syndrome 11
• Congenital heart defects, multiple types, 7
• Corneal dystrophy, Meesmann 2
• Deafness, autosomal dominant, 7
• Deafness, autosomal dominant, 75
• Deafness, autosomal dominant, 76
• Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies
• Epileptic encephalopathy, early infantile, 83
• Epileptic encephalopathy, early infantile, 84
• Heyn-Sproul-Jackson syndrome
• Hydrocephalus, normal pressure, 1
• Hypotrichosis 5
• Imagawa-Matsumoto syndrome
• Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
• Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type
• Intellectual developmental disorder 61
• Intellectual developmental disorder 62
• Intellectual developmental disorder with hypotonia and behavioral abnormalities
• Joubert syndrome 36
• Juvenile arthritis
• Keratitis-ichthyosis-deafness syndrome, autosomal recessive
• Liang-Wang syndrome
• Long QT syndrome 16
• Lymphatic malformation 8
• Mitochondrial complex I deficiency, nuclear type 34
• Mitochondrial complex III deficiency, nuclear 10
• Myopia 27
• Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
• Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy
• Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
• Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements
• Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity
• Neuromuscular disease and ocular or auditory anomalies with or without seizures
• Neutropenia, severe congenital 8, autosomal dominant
• Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures
• Poirier-Bienvenu neurodevelopmental syndrome
• Retinitis pigmentosa 88
• Spastic paraplegia 81, autosomal recessive
• Spastic paraplegia 82, autosomal recessive
• Spermatogenic failure 1
• Spermatogenic failure 42
• Spermatogenic failure 43
• Spondyloepimetaphyseal dysplasia, Isidor-Toutain type
• Structural brain anomalies with impaired intellectual development and craniosynostosis
• Ventricular tachycardia, catecholaminergic polymorphic, 6

Modified diseases:

• Corneal dystrophy, Meesmann -> Corneal dystrophy, Meesmann 1
• Sitosterolemia -> Sitosterolemia 1

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Lipidation' ('LIPID' in the flat file):

• 3'-prenyl-2',N2-cyclotryptophan

Headline

Genome integrity maintenance by HMCES

Apurinic or apyrimidinic sites, also known as abasic or AP sites, are one of the most common DNA lesions. They occur at a frequency of about 15,000 per day in human cells. In double-stranded DNA, the majority of AP sites are removed by base excision repair. After removal of the lesion, the undamaged strand is used as a template for repair synthesis. AP sites also form in single-stranded DNA (ssDNA), but until recently there was no known mechanism involved in their repair in this context. A major breakthrough in the field was reported last year in Cell.

Mohni et al. were interested in HMCES. HMCES full name is 'stem cell-specific 5-hydroxymethylcytosine-binding protein'. It was originally thought to be a regulator of 5-hydroxymethylcytosine. However, it had also been identified in the replisome, a large protein machine that carries out DNA replication. HMCES is conserved in almost all organisms, even in those that do not utilize methylcytosine for epigenetic control. Taken together, these observations suggested that HMCES could bear another crucial function, possibly in replication. Surprisingly HMCES knockout in cells did not affect DNA replication, nor cell division, but rather exacerbated cell sensitivity toward several DNA-damaging agents. Knockout cells accumulated DNA damage and exhibited increased genetic instability. Different DNA-damaging agents were tested and the only common kind of lesion they induced was the formation of AP sites.

HMCES appears to act as the initiating step of a replication-coupled repair mechanism for abasic sites in ssDNA. In eukaryotic cells, HMCES interacts with proliferating cell nuclear antigen (PCNA), an essential factor for replication, and travels with replication forks. When it senses AP sites in ssDNA, it covalently crosslinks to ssDNA AP sites generating a DNA-protein intermediate. The nature of this crosslink has been identified by crystallographic studies as a stable thiazolidine DNA-protein linkage formed between the N-terminal cysteine and the aldehyde form of the AP deoxyribose. The crosslink is so stable that its resolution requires HMCES degradation via the proteasome. This sequence of events may appear counterintuitive. It is almost as if HMCES takes a bad situation and makes it worse. However, this crosslink effectively shields the lesion from endonucleases and error-prone trans-lesion bypass (TLS) polymerases, such as REV1 and REV3L, and prevents mutagenesis they might engender. The DNA repair mechanism acting downstream of HMCES is not known.

As of this release, human HMCES, as well as YedK, an Escherichia coli homolog have been updated and are available in UniProtKB/Swiss-Prot. The exact structure of the chemical crosslink was submitted to ChEBI where more details are provided.

UniProtKB news

Change of annotation topic 'Interaction'

The annotation topic 'Interaction' provides information about binary protein-protein interactions. This data is curated in the IntAct database and a quality-filtered subset is imported into UniProtKB at each release.

In the context of improving the functional annotation of different gene products in UniProtKB/Swiss-Prot, we have started to import more detailed data from IntAct. Our previous representation of a binary protein-protein interaction provided details only for the protein that was described in another entry. This left ambiguity in UniProtKB/Swiss-Prot entries that describe more than one protein (isoforms or/and products of proteolytic cleavage). To address this we now describe both interacting proteins by unique UniProtKB identifiers.

This change affects the three main UniProtKB distribution formats (text, XML, RDF). The details are described for each format in a separate section below. The following placeholders are used in the format descriptions:

• <Interactant> represents a UniProtKB protein.
  • <Accession> is a UniProtKB accession number.
  • <IsoId> is a UniProtKB isoform ID.
  • <ProductId> is a UniProtKB product ID.
  • <Gene> is either the gene name, ordered locus name or ORF name of the gene that encodes the UniProtKB protein (see Gene names).

• <Experiments> is the number of experiments in IntAct that support an interaction.

• <IntActId> is an IntAct protein ID.

Note: The format descriptions make use of POSIX ERE syntax.

Text format

Previous format:

CC   -!- INTERACTION:
CC       <Interactant>( \(xeno\))?; NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       <Interactant>( \(xeno\))?; NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       ...

The <Interactant> was described in the following way:

Self|(<Accession>|<IsoId>):(<Gene>|-)

Where Self represents a self-interaction and a dash is shown for proteins with an undefined <Gene>. xeno is an optional flag that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

New format:

CC   -!- INTERACTION:
CC       <Interactant>; <Interactant>;( Xeno;)? NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       <Interactant>; <Interactant>;( Xeno;)? NbExp=<Experiments>; IntAct=<IntActId>, <IntActId>;
CC       ...

Where

• the first <Interactant> is represented by:

  (<Accession>|<IsoId>|<ProductId>)
  

• the second <Interactant> is represented by:

  (<Accession>|<IsoId>|<ProductId> [<Accession>])(: <Gene>)?
  

Example: P11309

Binary interactions with different isoforms that are described in P11309.

Previous format:

CC   -!- INTERACTION:
CC       Q9BZS1-1:FOXP3; NbExp=3; IntAct=EBI-1018629, EBI-9695448;
CC       Q9UNQ0:ABCG2; NbExp=5; IntAct=EBI-1018633, EBI-1569435;

New format:

CC   -!- INTERACTION:
CC       P11309-1; Q9BZS1-1: FOXP3; NbExp=3; IntAct=EBI-1018629, EBI-9695448;
CC       P11309-2; Q9UNQ0: ABCG2; NbExp=5; IntAct=EBI-1018633, EBI-1569435;

Example: P27958 and Q9NPY3

Binary interaction with a product of proteolytic cleavage. Interactions involving products of proteolytic cleavage were previously not imported from IntAct, therefore only the new data/format is shown.

New data and format of P27958:

CC   -!- INTERACTION:
CC       PRO_0000037566; Q9NPY3: CD93; Xeno; NbExp=2; IntAct=EBI-6377335, EBI-1755002;

New data and format of Q9NPY3:

CC   -!- INTERACTION:
CC       Q9NPY3; PRO_0000037566 [P27958]; Xeno; NbExp=2; IntAct=EBI-1755002, EBI-6377335;

XML format

The UniProtKB XSD represents a binary interaction with:

• two interactant elements of interactantType

• a boolean organismsDiffer element that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

• an experiments element that gives the number of experiments in IntAct that support an interaction.

The interactantType uses an interactantGroup to represent a sequence of:

• an id element

• an optional label element

We have added an optional dbReference element to the interactantGroup to allow us to represent the UniProtKB <Accession> for a <ProductId>:

<xs:group name="interactantGroup">
        <xs:sequence>
            <xs:element name="id" type="xs:string"/>
            <xs:element name="label" type="xs:string" minOccurs="0"/>
            <xs:element name="dbReference" type="dbReferenceType" minOccurs="0"/>
        </xs:sequence>
    </xs:group>

Previous format:

<comment type="interaction">
  <interactant intactId="<IntActId>"/>
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId></id>
    <label><Gene></label>
  </interactant>
  <organismsDiffer>true|false</organismsDiffer>
  <experiments><Experiments></experiments>
</comment>

New format:

<comment type="interaction">
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId>|<ProductId></id>
  </interactant>
  <interactant intactId="<IntActId>">
    <id><Accession>|<IsoId>|<ProductId></id>
    <label><Gene></label>
    <!-- If <id> is a <ProductId>: -->
    <dbReference type="UniProtKB" id="<Accession>"/>
  </interactant>
  <organismsDiffer>true|false</organismsDiffer>
  <experiments><Experiments></experiments>
</comment>

Example: P11309

Binary interactions with different isoforms that are described in P11309.

Previous format:

<comment type="interaction">
  <interactant intactId="EBI-1018629"/>
  <interactant intactId="EBI-9695448">
    <id>Q9BZS1-1</id>
    <label>FOXP3</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>3</experiments>
</comment>
<comment type="interaction">
  <interactant intactId="EBI-1018633"/>
  <interactant intactId="EBI-1569435">
    <id>Q9UNQ0</id>
    <label>ABCG2</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>5</experiments>
</comment>

New format:

<comment type="interaction">
  <interactant intactId="EBI-1018629">
    <id>P11309-1</id>
  </interactant>
  <interactant intactId="EBI-9695448">
    <id>Q9BZS1-1</id>
    <label>FOXP3</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>3</experiments>
</comment>
<comment type="interaction">
  <interactant intactId="EBI-1018633">
    <id>P11309-2</id>
  </interactant>
  <interactant intactId="EBI-1569435">
    <id>Q9UNQ0</id>
    <label>ABCG2</label>
  </interactant>
  <organismsDiffer>false</organismsDiffer>
  <experiments>5</experiments>
</comment>

Example: P27958 and Q9NPY3

Binary interaction with a product of proteolytic cleavage. Interactions involving products of proteolytic cleavage had previously not been imported from IntAct, therefore only the new data/format is shown.

New data and format of P27958:

<comment type="interaction">
  <interactant intactId="EBI-6377335">
    <id>PRO_0000037566</id>
  </interactant>
  <interactant intactId="EBI-1755002">
    <id>Q9NPY3</id>
    <label>CD93</label>
  </interactant>
  <organismsDiffer>true</organismsDiffer>
  <experiments>2</experiments>
</comment>

New data and format of Q9NPY3:

<comment type="interaction">
  <interactant intactId="EBI-1755002">
    <id>Q9NPY3</id>
  </interactant>
  <interactant intactId="EBI-6377335">
    <id>PRO_0000037566</id>
    <dbReference type="UniProtKB" id="P27958"/>
  </interactant>
  <organismsDiffer>true</organismsDiffer>
  <experiments>2</experiments>
</comment>

RDF format

The UniProt RDF schema ontology represents a binary interaction with an interaction property whose rdfs:range is the Interaction class. This class is the domain of the following properties that describe the interaction:

• participant refers to an object of type Participant.

• xeno is a boolean that indicates that the interacting proteins are derived from different species. This may be due to the experimental set-up or may reflect a pathogen-host interaction.

• experiments gives the number of experiments in IntAct that support an interaction.

A Participant is identified by its unique IntAct identifier. It also refers to the corresponding UniProtKB protein which is represented as described in the news article about the functional annotation of different gene products in UniProtKB/Swiss-Prot. An optional rdfs:label property may provide the gene name, ordered locus name or ORF name of the gene that encodes the UniProtKB protein.

The RDF schema ontology required no changes to represent the more detailed data that we now import from IntAct. Due to the symmetry of binary interactions, the UniProt SPARQL server already provided access to the full details about both interacting proteins. We have however taken this opportunity to normalize the URI of a binary interaction so that the two UniProtKB entries that describe the interacting proteins refer to the interaction with the same URI:

Previous format:

<<Accession>#interaction-<IntActId>-<IntActId>> .

New format:

<http://purl.uniprot.org/intact/<IntActId>-<IntActId>> .

Example: P11309 and Q8N9N5

Previous format:

P11309:

<P11309#interaction-696621-744695>

Q8N9N5:

<Q8N9N5#interaction-744695-696621>

New format:

P11309 and Q8N9N5:

<http://purl.uniprot.org/intact/EBI-696621-EBI-744695>

Cross-references to Antibodypedia

Cross-references have been added to Antibodypedia, a portal providing access to publicly available research antibodies towards human protein targets from many different providers.

Antibodypedia is available at https://www.antibodypedia.com/.

The format of the explicit links is:

Resource abbreviation	Antibodypedia
Resource identifier	Resource identifier
Optional information 1	Number of antibodies

Example: P04626

Show all entries having a cross-reference to Antibodypedia.

Text format

Example: P04626

DR   Antibodypedia; 740; 5394 antibodies.

XML format

Example: P04626

<dbReference type="Antibodypedia" id="740">
   <property type="antibodies" value="5394 antibodies"/>
</dbReference>

RDF format

Example: P04626

uniprot:P04626
  rdfs:seeAlso <http://purl.uniprot.org/antibodypedia/740> .

<http://purl.uniprot.org/antibodypedia/740>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Antibodypedia> ;
  rdfs:comment "5394 antibodies" .

Cross-references to MetOSite

Cross-references have been added to MetOSite, a database of methionine sulfoxide sites. Each collected site has been classified according to the effect of its sulfoxidation on the biological properties of the modified protein. Thus, MetOSite documents cases where the sulfoxidation of methionine leads to gain or loss of activity, increased or decreased protein-protein interaction susceptibility, and to changes in protein stability or in subcellular location.

MetOSite is available at https://metosite.uma.es/.

The format of the explicit links is:

Resource abbreviation	MetOSite
Resource identifier	UniProtKB accession number

Example: P10987

Show all entries having a cross-reference to MetOSite.

Text format

Example: P10987

DR   MetOSite; P10987; -.

XML format

Example: P10987

<dbReference type="MetOSite" id="P10987"/>

RDF format

Example: P10987

uniprot:P10987
  rdfs:seeAlso <http://purl.uniprot.org/metosite/P10987> .
<http://purl.uniprot.org/metosite/P10987>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/MetOSite> .

Cross-references to PHI-base

Cross-references have been added to PHI-base, a database providing expertly curated molecular and biological information on genes proven to affect the outcome of pathogen-host interactions.

PHI-base is available at http://www.phi-base.org/.

The format of the explicit links is:

Resource abbreviation	PHI-base
Resource identifier	Resource identifier

Example: Q00310

Show all entries having a cross-reference to PHI-base.

Text format

Example: Q00310

DR   PHI-base; PHI:104; -.

XML format

Example: Q00310

<dbReference type="PHI-base" id="PHI:104"/>

RDF format

Example: Q00310

uniprot:Q00310
  rdfs:seeAlso <http://purl.uniprot.org/phi-base/PHI:104> .
<http://purl.uniprot.org/phi-base/PHI:104>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PHI-base> .

Change to the cross-references to Human Protein Atlas (HPA)

We have changed the way we present the Human Protein Atlas database cross-references. Links between UniProtKB entries and HPA used to be established by HPA antibody identifier, but are now based on Ensembl Gene identifiers.

We have also introduced an additional field in these cross-references to indicate the level of RNA tissue specificity. The RNA specificity category is based on mRNA expression levels in the analyzed samples. The categories include: 'Tissue enriched', 'Group enriched', 'Tissue enhanced', 'Low tissue specificity' and 'Not detected'. For more details on these categories, see the Classification of transcriptomics data by Human Protein Atlas.

Text format

Example: Q9NSG2

Previous format:

DR   HPA; HPA023778; -.
DR   HPA; HPA024451; -.

New format:

DR   HPA; ENSG00000000460; Tissue enhanced (lymphoid).

XML format

Example: Q9NSG2

Previous format:

<dbReference type="HPA" id="HPA023778"/>
<dbReference type="HPA" id="HPA024451"/>

New format:

<dbReference type="HPA" id="ENSG00000000460">
  <property type="expression patterns" value="Tissue enhanced (lymphoid)"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: Q9NSG2

Previous format:

uniprot:Q9NSG2
  rdfs:seeAlso <http://purl.uniprot.org/hpa/HPA023778> ,
               <http://purl.uniprot.org/hpa/HPA024451> .
<http://purl.uniprot.org/hpa/HPA023778>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> .
<http://purl.uniprot.org/hpa/HPA024451>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> .

New format:

uniprot:Q9NSG2
  rdfs:seeAlso <http://www.proteinatlas.org/ENSG00000000460> .
<http://www.proteinatlas.org/ENSG00000000460>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/HPA> ;
  rdfs:comment "Tissue enhanced (lymphoid)" .

Changes to the controlled vocabulary of human diseases

New diseases:

• Ciliary dyskinesia, primary, 42
• Ciliary dyskinesia, primary, 43
• Epileptic encephalopathy, early infantile, 81
• Epileptic encephalopathy, early infantile, 82
• Hemolytic anemia due to glutathione reductase deficiency
• Hydrocephalus, congenital communicating, 1
• Intellectual developmental disorder, autosomal recessive 72
• Intellectual developmental disorder with impaired language and dysmorphic facies
• Intellectual developmental disorder with short stature and behavioral abnormalities
• Intellectual developmental disorder with speech delay, autism and dysmorphic facies
• Leukodystrophy, hypomyelinating, 19, transient infantile
• Megabladder, congenital
• Megacystis-microcolon-intestinal hypoperistalsis syndrome
• Microphthalmia, syndromic, 15
• Mitochondrial complex V deficiency, nuclear type 6
• Myopathy, congenital, with structured cores and Z-line abnormalities
• Myopathy, distal, 6, adult onset, autosomal dominant
• Neurodevelopmental disorder with absent language and variable seizures
• Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
• Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
• Neurodevelopmental disorder with macrocephaly and with or without seizures
• Neurodevelopmental disorder with non-specific brain abnormalities and with or without seizures
• Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies
• Neuronal intranuclear inclusion disease
• Neurooculocardiogenitourinary syndrome
• Premature ovarian failure 16
• Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 5
• Retinitis pigmentosa 87 with choroidal involvement
• Short stature and microcephaly with genital anomalies
• Sitosterolemia 2
• Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy
• Zimmermann-Laband syndrome 3

Modified diseases:

• 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia -> 3-methylglutaconic aciduria 7
• Cowchock syndrome -> Charcot-Marie-Tooth disease, X-linked recessive, 4, with or without cerebellar ataxia
• Developmental delay, intellectual disability, obesity, and dysmorphic features -> Chung-Jansen syndrome
• Developmental delay with short stature, dysmorphic features, and sparse hair -> Developmental delay with short stature, dysmorphic facial features, and sparse hair
• Ischiocoxopodopatellar syndrome -> Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension
• Mental retardation, X-linked, syndromic, 36 -> Basilicata-Akhtar syndrome
• Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration -> Metabolic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration
• Neuropathy, hereditary motor and sensory, 6A -> Neuropathy, hereditary motor and sensory, 6A, with optic atrophy
• Seizures, scoliosis, and macrocephaly syndrome -> Seizures, scoliosis, and macrocephaly/microcephaly syndrome
• Spondyloepimetaphyseal dysplasia MATN3-related -> Spondyloepimetaphyseal dysplasia, MATN3-related
• Spondyloepimetaphyseal dysplasia Missouri type -> Spondyloepimetaphyseal dysplasia, Missouri type
• Spondyloepimetaphyseal dysplasia short limb-hand type -> Spondyloepimetaphyseal dysplasia, short limb-hand type

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Thiazolidine linkage to a ring-opened DNA abasic site
• Deoxyhypusine

RDF news

Change of URIs for the Human Protein Atlas (HPA) database

For historic reasons, UniProt had to generate URIs to cross-reference databases that did not have an RDF representation. Our policy is to replace these by the URIs generated by the cross-referenced database once it starts to distribute an RDF representation of its data.

The URIs for the Human Protein Atlas database have therefore been updated from:

http://purl.uniprot.org/hpa/<ID>

to:

http://www.proteinatlas.org/<ID>

If required for backward compatibility, you will be able to use the following query to add the old URIs:

PREFIX owl:<http://www.w3.org/2002/07/owl#>
PREFIX up:<http://purl.uniprot.org/core/>
INSERT
{
   ?protein rdfs:seeAlso ?old .
   ?old owl:sameAs ?new .
   ?old up:database <http://purl.uniprot.org/database/HPA> .
}
WHERE
{
   ?protein rdfs:seeAlso ?new .
   ?new up:database <http://purl.uniprot.org/database/HPA> .
   BIND(iri(concat('http://purl.uniprot.org/hpa/', substr(str(?new),29))) AS ?old)
}

The dereferencing of existing http://purl.uniprot.org/hpa/<ID> URIs will be maintained.

Standardized MD5 checksums in UniProt RDF

The UniProt databases UniProtKB, UniRef and UniParc have historically provided a CRC-64 checksum for the amino acid sequences. In the UniParc RDF representation we had already introduced an MD5 checksum, and we have now replaced it with a SPARQL 1.1 compliant MD5 representation (lowercase string) and use this across all databases. This allows to use the MD5 function defined in SPARQL 1.1 to check that the sequence string is not corrupted, without the need to use the lowercase (LCASE) function and a cast to string, as it was formerly the case:

PREFIX rdf:<http://www.w3.org/1999/02/22-rdf-syntax-ns#>
PREFIX up:<http://purl.uniprot.org/core/>
SELECT ?computedMD5 ((?uniprotMD5 = ?computedMD5) AS ?md5SumsMatch)
WHERE
{
  ?protein a up:Protein ;
    up:sequence ?sequence .
  ?sequence rdf:value ?value ;
    up:md5Checksum ?uniprotMD5 .
  BIND(MD5(?value) AS ?computedMD5)
}

Headline

Coronavirus SARS-CoV-2 in UniProtKB

At the end of 2019, a novel coronavirus (nCoV) of animal origin started infecting humans, initiating a severe outbreak in China. nCoV infection can result in severe and even fatal respiratory diseases, such as acute respiratory distress syndrome. The virus is highly contagious and transmission occurs via airborne droplets and contact. On January 30^th, 2019-nCoV was designated a global health emergency by the WHO. On February 11^th, the WHO called the disease caused by the virus COVID-19, and the virus itself was named Severe Acute Respiratory Syndrome-related coronavirus 2 or SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV).

SARS-CoV-2 belongs to the large family of Coronaviridae, genus Betacoronavirus. This genus comprises mainly vertebrate respiratory viruses, including HCoV-OC43, which is responsible for 10% of common colds, and SARS, which caused an epidemic in 2003, resulting in over 8,000 infected individuals in 26 countries. The novel coronavirus genome has been sequenced. Its close similarity to SARS suggests it has emerged from the same reservoir, namely bats.

With a size of 30 kb, coronaviruses have the largest RNA genomes known to date. The genome encodes a polyprotein 1a that can be elongated by ribosomal frameshifting to produce polyprotein 1ab. The short and elongated polyproteins contain 11 and 15 chains, respectively, and are dedicated to viral RNA transcription and replication, while controlling the host antiviral defense. A strategy used by the virus to escape host cell innate immunity is to induce the formation of a specialized intracellular compartment from the endoplasmic reticulum, called endoplasmic spherules, which protects viral dsRNA replication intermediates. Later on subgenomic mRNAs are translated to produce virion structural proteins and yet another set of immune modulatory factors. Virions are assembled at the ER-Golgi intermediate compartment (or ERGIC) and exported out of the cell. The freshly exported virion is not yet infectious. Its surface is covered by spikes, giving the impression a crown (corona in Latin, hence its name), but spike proteins have to be cleaved in order to become functional and to confer infectivity on the virion. The activating proteolytic cleavages occur in the extracellular space.

It is at the level of spike proteins that SARS-CoV-2 diverges from SARS, differing in both amino acid sequence and glycosylation. The SARS-CoV-2 spike protein cleavage site comprises several arginines, making it an excellent substrate for many host proteases. This feature is predicted to enhance virus tropism and virulence. SARS-CoV-2 interacts with the same host receptor as SARS, ACE2, which presumably explains why both viruses infect lungs, as well as the small intestine and kidney. The functions of several other SARS-CoV-2 proteins are still unclear and need further investigations. Among them is SARS-CoV-2 NS8 protein, which shares sequence similarity with some Bat-hosted coronavirus NS8 proteins, but is entirely different from SARS NS8a or NS8b. Thus, in spite of many similarities to SARS and other coronaviruses, SARS-CoV-2 displays unique molecular features that lead to unpredictable behavior during infection.

SARS-CoV-2 protein sequences from the current public health emergency have been annotated in UniProtKB and made available as a pre-release dataset on the UniProt FTP site. These entries will be available in the usual file formats as part of release 2020_02.

UniProt release news

Change of release cycle

Starting with release 2020_01 of February 26th, UniProt releases are published every 8 weeks. Release 2020_02 is scheduled for April 22nd, 2020.

See also: How frequently is UniProt released? What is the synchronization delay with other databases?

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Abdominal obesity-metabolic syndrome 4
• Cortical dysplasia, complex, with other brain malformations 10
• Diarrhea 11, malabsorptive, congenital
• Diencephalic-mesencephalic junction dysplasia syndrome 2
• Deafness, autosomal dominant, 27
• Epilepsy, familial adult myoclonic, 3
• Epilepsy, familial adult myoclonic, 4
• Immunodeficiency 65
• Infantile liver failure syndrome 3
• Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies
• Lessel-Kubisch syndrome
• Lower urinary tract obstruction, congenital
• Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
• Noonan syndrome 12
• Oculopharyngodistal myopathy 1
• Osteogenesis imperfecta 20
• Pancreatic cancer 5
• Pontocerebellar hypoplasia 13
• Retinitis pigmentosa 86
• Rothmund-Thomson syndrome 1
• Siddiqi syndrome
• Snijders Blok-Fisher syndrome.
• Spermatogenic failure 39
• Spermatogenic failure 40
• Spermatogenic failure 41
• Usher syndrome 1M
• Weiss-Kruszka syndrome

Deleted disease

• Popov-Chang syndrome

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• N6-lactoyllysine

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (Cys-His) -> 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (His-Cys)

Headline

Thicker than water

We know about blood types and their incompatibility; transfusing someone who is O- with AB+ blood can be lethal. The ABO alleles present on chromosome 9 decide our blood type. The A and B antigens are a set of red blood cell surface carbohydrates ending in α-1,3-linked N-acetylgalactosamine and α-1,3-linked galactose respectively, while type O blood has neither of these cell surface sugars. Sequence variations in the ABO gene determine if the encoded protein has α-1,3-N-acetylgalactosaminyltransferase activity and makes type A blood, or if it has α-1,3-galactosyltransferase activity and makes type B blood. When both alleles are present, we make type AB blood. Deletion of a single G nucleotide in the ABO gene leads to a truncated inactive product and type O blood, which has the non-modified H antigen.

To improve the usability of blood, people have tried for years to find a way to enzymatically convert A or B blood to type O; it seems an obvious way to increase the supply of universal donor (which would still require Rhesus matching). While such enzymes have been found, they are not yet ideal, as they either work at high concentration or have very specific buffer requirements, not met by blood.

By screening human fecal metagenomic libraries, Rahfeld et al. have isolated a pair of enzymes from the obligate gut anaerobe Flavonifractor plautii that efficiently converts the A to H antigen (type O). The first enzyme (A type blood N-acetyl-alpha-D-galactosamine deacetylase, ADAC) deacylates all A antigen subtypes tested (and there are many), while the second enzyme (A type blood alpha-D-galactosamine galactosaminidase, AGAL) removes the residual galactosamine moiety. This reaction can occur on red blood cells and in blood, as opposed to a buffer system, and at low enzyme concentration, and thus shows promise for uses in blood production. Further testing is underway, and we still need a way to remove the B antigen, but this could well help increase the flexibility of our blood supply. It still won't solve the world shortage of blood, only more donors can do that...

As of this release, ADAC and AGAL have been annotated and are available in UniProtKB/Swiss-Prot.

UniProtKB news

Change of FT and CC sections in UniProtKB text format

We have changed the format of the FT and CC section of the UniProtKB text files. The changes of the FT section likely affects all parsers, and software will have to be adapted accordingly. The changes of the CC section are smaller, but may also require code adaptations depending on the CC annotation types that you parse.

The motivation for this change is described in the section "Functional annotation of different gene products in UniProtKB/Swiss-Prot" below, where you can also find the technical details and examples under the heading Text format.

Change of line length in UniProtKB text format

Historically, the lines of the UniProtKB text format have been wrapped at 75 characters for technical reasons (terminal screen size and data processing capabilities). When these technical restrictions vanished, we introduced exceptions for data like URLs, protein names and cross-references where line wrapping does not improve readability. These lines can be up to 255 characters long, but most lines are still wrapped at 75 characters for readability. We have now increased the maximum number of characters for wrapped lines to 80 in the context of the format change of the FT section of the UniProtKB text format for the functional annotation of different gene products in UniProtKB/Swiss-Prot described below.

Functional annotation of different gene products in UniProtKB/Swiss-Prot

To reduce database redundancy, the UniProtKB/Swiss-Prot policy is to describe, whenever possible, all protein products that are encoded by one gene in a given species in a single entry. This includes isoforms generated by alternative promoter usage, alternative splicing, alternative initiation and ribosomal frameshifting. We assign a name and a unique identifier to each isoform and choose one of them to be the canonical sequence that is shown in the UniProtKB text and XML format (the RDF format shows all sequences). All positional annotations in the entry referred to this canonical sequence until this release. Some gene products are precursors that are processed by proteolytic cleavage to generate the biologically active product(s). These products are described by their location on the sequence, a name and a unique identifier.

When isoforms, or products of proteolytic cleavage, are known to differ in their function or other characteristics, we generally describe this in the text of the respective annotations. To make this information also accessible to software applications, we adapted the UniProtKB text format to describe the product to which an annotation applies in a computer-processable way. The schemas of the XML and RDF format already supported this and required no changes. The following sections describe the changes for the text format and how the data is represented in the XML and RDF format.

Text format

Isoforms are described in ALTERNATIVE PRODUCTS annotations in the CC section. The products of proteolytic cleavage are described in PEPTIDE and CHAIN annotations in the FT section. All three annotation types provide a name (<ProductName>) and a unique ID (<ProductId>) for the product that they describe:

• ALTERNATIVE PRODUCTS annotations show the name of an isoform in the Name field and its ID in the IsoId field.

  CC   -!- ALTERNATIVE PRODUCTS:
  ...
  CC       Name=<ProductName>;
  CC         IsoId=<ProductId>; Sequence=Displayed;
  

• PEPTIDE and CHAIN annotations showed the name of a proteolytic cleavage product in the <Description> field and its ID in the FTId field in the previous text format:

  FT   CHAIN       <B>    <E>       <ProductName>.
  FT                                /FTId=<ProductId>.
  

  In the new text format that is described in more details in the FT section they are shown in the /note= and /id= qualifiers, respectively:

  FT   CHAIN           <B>..<E>
  FT                   /note="<ProductName>"
  FT                   /id="<ProductId>"
  

Example: O60443

CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=Long;
CC         IsoId=O60443-1; Sequence=Displayed;
CC       Name=2; Synonyms=Short;
CC         IsoId=O60443-2; Sequence=VSP_004190;
CC         Note=No experimental confirmation available.;
CC       Name=3;
CC         IsoId=O60443-3; Sequence=VSP_044276;
...
FT   CHAIN         1    496       Gasdermin-E.
FT                                /FTId=PRO_0000148178.
FT   CHAIN         1    270       Gasdermin-E, N-terminal.
FT                                {ECO:0000269|PubMed:27281216,
FT                                ECO:0000305|PubMed:28459430}.
FT                                /FTId=PRO_0000442786.
FT   CHAIN       271    496       Gasdermin-E, C-terminal.
FT                                {ECO:0000305|PubMed:28459430}.
FT                                /FTId=PRO_0000442787.

CC section

The annotation types in the CC section describe a product by its name (isoform names are prefixed with the term "Isoform"). In the format descriptions below this name is represented by <ProductName>. Different products are described in separate annotations (see FUNCTION and BIOPHYSICOCHEMICAL PROPERTIES examples).

All annotation types of the CC section start with:

CC   -!- <TYPE>:

Where <TYPE> is a value from the controlled vocabulary of annotation types.

In some annotation types the content of the annotation used to directly follow the <TYPE>, and lines were wrapped at 75 chars:

CC   -!- <TYPE>: <Content>

In the new format a <ProductName> may be added between the <TYPE> and the <Content> and lines are wrapped at 80 chars (see Change of line length in UniProtKB text format ):

CC   -!- <TYPE>: [<ProductName>]: <Content>

The <ProductName> is surrounded by square brackets and separated by a colon from the <Content> to make it possible to parse it with a POSIX ERE like this one:

^CC   -!- ([^:]+):(?: \[(.+?)\]:)? (.+)

Where $1=<TYPE>, $2=<ProductName>, $3=<Content>.

In annotation types where the content is structured as a list of different fields that are formatted according to custom rules for better readability, the annotation content starts on a new line:

CC   -!- <TYPE>:
CC       <Content>

In the new format a <ProductName> may be added after the <TYPE> and this line is not wrapped (i.e. it may in rare cases exceed 80 chars).

CC   -!- <TYPE>: [<ProductName>]:
CC       <Content>

The format of the <Content> remains unchanged.

A <ProductName> cannot be added to ALTERNATIVE PRODUCTS and INTERACTION annotations. The INTERACTION format will be adapted in a different way to describe binary interactions that involve isoforms and/or products of proteolytic cleavage (see Change of annotation topic 'Interaction' ).

Please note that the previous text format of SUBCELLULAR LOCATION, COFACTOR and MASS SPECTROMETRY annotations already allowed to specify a product name/ID, but we have adapted it to be consistent with all other annotation types.

Representative examples for different annotation types are shown here:

FUNCTION

Example: Q96F85

CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=CRIP1a;
CC         IsoId=Q96F85-1; Sequence=Displayed;
CC       Name=2; Synonyms=CRIP1b;
CC         IsoId=Q96F85-2; Sequence=VSP_035598;

Previous format:

CC   -!- FUNCTION: Isoform 1 suppresses cannabinoid receptor CNR1-mediated
CC       tonic inhibition of voltage-gated calcium channels. Isoform 2 does
CC       not have this effect. {ECO:0000269|PubMed:17895407}.

New format:

CC   -!- FUNCTION: [Isoform 1]: Suppresses cannabinoid receptor CNR1-mediated
CC       tonic inhibition of voltage-gated calcium channels.
CC       {ECO:0000269|PubMed:17895407}.
CC   -!- FUNCTION: [Isoform 2]: Does not suppress cannabinoid receptor CNR1-
CC       mediated tonic inhibition of voltage-gated calcium channels.
CC       {ECO:0000269|PubMed:17895407}.

DISEASE

Example: P35555

FT   CHAIN      2732   2871       Asprosin. {ECO:0000305|PubMed:27087445,
FT                                ECO:0000305|PubMed:9817919}.
FT                                /FTId=PRO_0000436882.

Previous format:

CC   -!- DISEASE: Marfan lipodystrophy syndrome (MFLS) [MIM:616914]: A
CC       syndrome characterized by congenital ...
CC       Note=The disease is caused by mutations affecting the gene
CC       represented in this entry. Asprosin: Mutations specifically affect
CC       Asprosin, a hormone peptide present at the C-terminus of
CC       Fibrillin-1 chain, which is cleaved from Fibrillin-1 following
CC       secretion (PubMed:27087445). {ECO:0000269|PubMed:27087445}.

New format:

CC   -!- DISEASE: [Asprosin]: Marfan lipodystrophy syndrome (MFLS) [MIM:616914]:
CC       A syndrome characterized by congenital ...
CC       Note=The disease is caused by mutations affecting the gene represented
CC       in this entry. {ECO:0000269|PubMed:27087445}.

SUBCELLULAR LOCATION

Please note that the previous text format of SUBCELLULAR LOCATION annotations already allowed to describe a product by its name in the optional first field. To be consistent with all other annotation types we have added square brackets around the product name.

Example: Q13421

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3; Synonyms=SMRP;
CC         IsoId=Q13421-2; Sequence=VSP_021059, VSP_021060;
...
FT   CHAIN        37    286       Megakaryocyte-potentiating factor.
FT                                /FTId=PRO_0000253560.

Previous format:

CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor.
CC       Golgi apparatus.
CC   -!- SUBCELLULAR LOCATION: Megakaryocyte-potentiating factor: Secreted.
CC   -!- SUBCELLULAR LOCATION: Isoform 3: Secreted.

New format:

CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Golgi
CC       apparatus.
CC   -!- SUBCELLULAR LOCATION: [Megakaryocyte-potentiating factor]: Secreted.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted.

MASS SPECTROMETRY

Please note that the previous text format of MASS SPECTROMETRY annotations already allowed to describe a product (by its sequence range and an optional isoform ID) in the Range field. To be consistent with all other annotation types we have replaced the Range field by a <ProductName> field.

Example: P09493

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3; Synonyms=Fibroblast, TM3;
CC         IsoId=P09493-3; Sequence=VSP_006577, VSP_006579;

Previous format:

CC   -!- MASS SPECTROMETRY: Mass=32875.93; Method=MALDI; Range=1-284
CC       (P09493-3); Evidence={ECO:0000269|PubMed:11840567};

New format:

CC   -!- MASS SPECTROMETRY: [Isoform 3]: Mass=32875.93; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:11840567};

RNA EDITING

Example: Q9P225

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=3;
CC         IsoId=Q9P225-3; Sequence=VSP_031913, VSP_031914, VSP_031915;

Previous format:

CC   -!- RNA EDITING: Modified_positions=Not_applicable; Note=Exon 13
CC       included in isoform 3 is extensively edited in brain.
CC       {ECO:0000269|PubMed:20835228};

New format:

CC   -!- RNA EDITING: [Isoform 3]: Modified_positions=Not_applicable; Note=Exon
CC       13 is extensively edited in brain. {ECO:0000269|PubMed:20835228};

WEB RESOURCE

Example: P50570

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=P50570-1; Sequence=Displayed;

Previous format:

CC   -!- WEB RESOURCE: Name=The UMD-DNM2-isoform 1 mutations database;
CC       URL="http://www.umd.be/DNM2/";

New format:

CC   -!- WEB RESOURCE: [Isoform 1]: Name=The UMD-DNM2-isoform 1 mutations
CC       database;
CC       URL="http://www.umd.be/DNM2/";

CATALYTIC ACTIVITY

Example: Q2YHF0

FT   CHAIN      1475   2092       Serine protease NS3.
FT                                {ECO:0000250|UniProtKB:P29990}.
FT                                /FTId=PRO_0000268140.
...
FT   CHAIN      2488   3387       RNA-directed RNA polymerase NS5.
FT                                {ECO:0000250|UniProtKB:P29990}.
FT                                /FTId=PRO_0000268144.

Previous format:

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which
CC         each of the Xaa can be either Arg or Lys and Yaa can be either
CC         Ser or Ala.; EC=3.4.21.91;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA-
CC         COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557,
CC         ChEBI:CHEBI:83400; EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU00539};

New format:

CC   -!- CATALYTIC ACTIVITY: [Serine protease NS3]:
CC       Reaction=Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which each of
CC         the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala.;
CC         EC=3.4.21.91;
CC   -!- CATALYTIC ACTIVITY: [RNA-directed RNA polymerase NS5]:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA-
CC         COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:83400;
CC         EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539};

COFACTOR

Please note that the previous text format of COFACTOR annotations already allowed to describe a product by its name in the optional first field. To be consistent with all other annotation types we have added square brackets around the product name.

Example: P26662

FT   CHAIN      1027   1657       Serine protease NS3. {ECO:0000255}.
FT                                /FTId=PRO_0000037644.
FT   CHAIN      1658   1711       Non-structural protein 4A. {ECO:0000255}.
FT                                /FTId=PRO_0000037645.

Previous format:

CC   -!- COFACTOR: Serine protease NS3:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:9060645};
CC       Note=Binds 1 zinc ion. {ECO:0000269|PubMed:9060645};
CC   -!- COFACTOR: Non-structural protein 5A:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion in the NS5A N-terminal domain.
CC       {ECO:0000250};

New format:

CC   -!- COFACTOR: [Serine protease NS3]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:9060645};
CC       Note=Binds 1 zinc ion. {ECO:0000269|PubMed:9060645};
CC   -!- COFACTOR: [Non-structural protein 5A]:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion in the NS5A N-terminal domain. {ECO:0000250};

BIOPHYSICOCHEMICAL PROPERTIES

Example: Q9ULC5

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1; Synonyms=ACSL5b, ACSL5-fl;
CC         IsoId=Q9ULC5-1; Sequence=Displayed;
...
CC       Name=3; Synonyms=ACSL5delta20;
CC         IsoId=Q9ULC5-4; Sequence=VSP_038233;

Previous format:

CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.11 uM for palmitic acid (isoform 1 at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.38 uM for palmitic acid (isoform 1 at pH 9.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.04 uM for palmitic acid (isoform 3 at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.15 uM for palmitic acid (isoform 3 at pH 8.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 9.5 (isoform 1), 7.5-8.5 (isoform 3).
CC         {ECO:0000269|PubMed:17681178};

New format:

CC   -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]:
CC       Kinetic parameters:
CC         KM=0.11 uM for palmitic acid (at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.38 uM for palmitic acid (at pH 9.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 9.5. {ECO:0000269|PubMed:17681178};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 3]:
CC       Kinetic parameters:
CC         KM=0.04 uM for palmitic acid (at pH 7.5)
CC         {ECO:0000269|PubMed:17681178};
CC         KM=0.15 uM for palmitic acid (at pH 8.5)
CC         {ECO:0000269|PubMed:17681178};
CC       pH dependence:
CC         Optimum pH is 7.5-8.5. {ECO:0000269|PubMed:17681178};

SEQUENCE CAUTION

Example: Q9NQS3

Previous format:

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=Q9NQS3-1; Sequence=Displayed;
...
CC       Name=3;
CC         IsoId=Q9NQS3-3; Sequence=VSP_046893, VSP_046894;
CC         Note=Ref.2 (BAC11404) sequence differs from that shown due to
CC         erroneous termination (Truncated C-terminus). {ECO:0000305};
...
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH17572.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

New format:

CC   -!- ALTERNATIVE PRODUCTS:
...
CC       Name=1;
CC         IsoId=Q9NQS3-1; Sequence=Displayed;
...
CC       Name=3;
CC         IsoId=Q9NQS3-3; Sequence=VSP_046893, VSP_046894;
...
CC   -!- SEQUENCE CAUTION: [Isoform 1]:
CC       Sequence=AAH17572.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC   -!- SEQUENCE CAUTION: [Isoform 3]:
CC       Sequence=BAC11404.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};

FT section

Note: The format descriptions make use of POSIX ERE syntax.

All positional annotations in the FT section previously referred to the canonical sequence that is shown in the UniProtKB entry. This was the text format of these annotation types:

FT   <TYPE>      <B>    <E>       (<Description>.)?( {<Evidences>}.)?
(FT                                /FTId=<Id>.)?

Where

• <TYPE> is a value from the controlled vocabulary of positional annotation types.
• <B> and <E> are amino acid positions on the canonical sequence. For most annotation types, they are the begin and end position of a sequence range, but they have other semantics for some types (e.g. CROSSLNK and DISULFID).
• <Description> may provide information in addition to that conveyed by the <TYPE> and the location <B> and <E>. This field is mandatory for some annotation types and optional for others.
• <Evidences> are optional and added between curly braces.
• <Id> is a unique annotation identifier that is mandatory for some annotation types, including CHAIN and PEPTIDE where it corresponds to the <ProductId>.

We have modified this format in order to describe amino acid positions on isoforms sequences. The new format is inspired by the INSDC's feature table format to enable code reuse:

FT   <TYPE>          <Location>
(FT                   /<Qualifier>(="<Value>")?)*

Where

• <TYPE> is a value from the controlled vocabulary of positional annotation types.
• <Location> is a sequence location on the canonical or an isoform sequence. We will use for now only a subset of the INSDC Location types: A <Location> must be either a single <Position> or a range of <Position> that may optionally be preceded by an isoform ID. The < and > symbols may be used with begin and end positions to indicate that the begin or end point is beyond the specified amino acid position. Please note that we have to extend the INSDC Location format with the ? symbol to allow us to represent all existing UniProtKB locations. This symbol may precede a <Position> to indicate that the exact position is unsure, or it may substitute the <Position> when the position is unknown.

  (<IsoformId>:)?((<|?)?<Position>|?)(..((>|?)?<Position>|?))?
  

• /<Qualifier> may provide information in addition to that conveyed by the <TYPE> and <Location>. While we will follow the format of the INSDC Qualifiers, we will introduce our own <Qualifier> types where necessary. For this format change, we will represent the existing data with 3 qualifiers:
  • /note= will show the content of the current <Description> field.
  • /evidence= will show the content of the current <Evidences> field.
  • /id= will show the content of the current /FTId= field.

In a future format change, we may introduce more <Location> and <Qualifier> types to structure the description of positional annotations further.

Lines are wrapped at 80 chars (see section Change of line length in UniProtKB text format above).

Example: P84077

This example illustrates the format change with a selection of representative positional annotation types that refer to the canonical sequence.

Previous format:

FT   INIT_MET      1      1       Removed. {ECO:0000244|PubMed:19413330,
FT                                ECO:0000244|PubMed:22223895,
FT                                ECO:0000269|PubMed:25255805,
FT                                ECO:0000269|PubMed:25807930}.
FT   CHAIN         2    181       ADP-ribosylation factor 1.
FT                                /FTId=PRO_0000207378.
...
FT   NP_BIND     126    129       GTP. {ECO:0000244|PDB:1HUR,
FT                                ECO:0000244|PDB:1RE0,
FT                                ECO:0000244|PDB:1U81,
FT                                ECO:0000244|PDB:3O47, ECO:0000305}.
...
FT   VARIANT      35     35       Y -> H (in PVNH8; decreased interaction
FT                                with GGA3; dbSNP:rs879036238).
FT                                {ECO:0000269|PubMed:28868155}.
FT                                /FTId=VAR_081272.
...
FT   HELIX         6      9       {ECO:0000244|PDB:1HUR}.

New format:

FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000244|PubMed:19413330,
FT                   ECO:0000244|PubMed:22223895, ECO:0000269|PubMed:25255805,
FT                   ECO:0000269|PubMed:25807930"
FT   CHAIN           2..181
FT                   /note="ADP-ribosylation factor 1"
FT                   /id="PRO_0000207378"
...
FT   NP_BIND         126..129
FT                   /note="GTP"
FT                   /evidence="ECO:0000244|PDB:1HUR, ECO:0000244|PDB:1RE0,
FT                   ECO:0000244|PDB:1U81, ECO:0000244|PDB:3O47, ECO:0000305"
...
FT   VARIANT         35
FT                   /note="Y -> H (in PVNH8; decreased interaction with GGA3;
FT                   dbSNP:rs879036238)"
FT                   /evidence="ECO:0000269|PubMed:28868155"
FT                   /id="VAR_081272"
...
FT   HELIX           6..9
FT                   /evidence="ECO:0000244|PDB:1HUR"

Example: P0C551

This example illustrates the use of the < and ? symbols in UniProtKB locations.

Previous format:

FT   SIGNAL       <1      ?       {ECO:0000250}.
FT   PROPEP        ?     17       {ECO:0000250}.
FT                                /FTId=PRO_0000293097.
FT   CHAIN        18    142       Acidic phospholipase A2 KBf-grIB.
FT                                /FTId=FTId=PRO_0000293098.

New format:

FT   SIGNAL          <1..?
FT                   /evidence="ECO:0000250"
FT   PROPEP          ?..17
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000293097"
FT   CHAIN           18..142
FT                   /note="Acidic phospholipase A2 KBf-grIB"
FT                   /id="PRO_0000293098"

Example: P12821

This example illustrates how positional annotations for isoforms are represented.

Previous format:

CC   -!- ALTERNATIVE PRODUCTS:
CC       ...
CC       Name=Testis-specific; Synonyms=ACE-T;
CC         IsoId=P12821-3, P22966-1;
CC         Sequence=VSP_035120, VSP_035121;
CC         Note=Variant in position: 32:S->P (in dbSNP:rs4317). Variant in
CC         position: 49:S->G (in dbSNP:rs4318).;
...
FT   VARIANT     154    154       A -> T (in dbSNP:rs13306087).
FT                                /FTId=VAR_029139.

New format:

CC   -!- ALTERNATIVE PRODUCTS:
CC       ...
CC       Name=Testis-specific; Synonyms=ACE-T;
CC         IsoId=P12821-3, P22966-1;
CC         Sequence=VSP_035120, VSP_035121;
...
FT   VARIANT         154
FT                   /note="A -> T (in dbSNP:rs13306087)"
FT                   /id="VAR_029139"
...
FT   VARIANT         P12821-3:32
FT                   /note="S -> P (in dbSNP:rs4317)"
FT                   /id="VAR_x"
FT   VARIANT         P12821-3:49
FT                   /note="S -> G (in dbSNP:rs4318)"
FT                   /id="VAR_y"

XML format

The UniProtKB XSD already allowed to describe the product to which an annotation applies and required no changes.

Isoforms are described in "alternative products" annotations. The products of proteolytic cleavage are described in "peptide" and "chain" annotations. All three annotation types provide a name (<ProductName>) and/or a unique ID (<ProductId>) for the product that they describe:

• "alternative products" annotations describe each isoform by an isoform element of isoformType. The isoformType describes the product IDs and names with sequences of id and name elements (where the first element in each sequence is the main product ID/name).

  <comment type="alternative products">
    ...
    <isoform>
      <id><ProductId></id>
      <id><OldProductId></id>
      <name><ProductName></name>
      <name><AlternativeProductName></name>
      ...
    </isoform>
    ...
  </comment>
  

• "peptide" and "chain" annotations show the name and ID of a proteolytic cleavage product in the description and id attributes of the featureType.

  <feature type="chain" description="<ProductName>" id="<ProductId>">
  ...
  </feature>
  

commentType

The commentType has two ways to indicate that the annotation applies to a specific product:

• An optional molecule element of moleculeType allows to describe a product by its name or/and unique ID. It is currently only used for "subcellular location" and "cofactor" annotations (see examples below). In the future it may be used for all annotations that are represented by commentType.

• An optional sequence of location elements of locationType allows to describe the sequence coordinates of an annotation. The locationType has an optional sequence attribute that is only set (to an isoform ID) when the coordinates are not for the canonical sequence. Sequence coordinates may currently be given for "rna editing", "sequence caution" and "mass spectrometry" annotations. In the future sequence caution and mass spectrometry annotations will no longer describe sequence coordinates.

subcellular location

Example: Q13421

<comment type="alternative products">
  ...
  <isoform>
    <id>Q13421-2</id>
    <name>3</name>
    <name>SMRP</name>
    <sequence type="described" ref="VSP_021059 VSP_021060"/>
    ...
  </isoform>
  ...
</comment>
...
<feature type="chain" description="Megakaryocyte-potentiating factor"
                      id="PRO_0000253560">
  <location>
    <begin position="37"/>
    <end position="286"/>
  </location>
</feature>

<comment type="subcellular location">
  <subcellularLocation>
    <location>Cell membrane</location>
    <topology>Lipid-anchor</topology>
    <topology>GPI-anchor</topology>
  </subcellularLocation>
  <subcellularLocation>
    <location>Golgi apparatus</location>
  </subcellularLocation>
</comment>
<comment type="subcellular location">
  <molecule>Megakaryocyte-potentiating factor</molecule>
  <subcellularLocation>
    <location>Secreted</location>
  </subcellularLocation>
</comment>
<comment type="subcellular location">
  <molecule>Isoform 3</molecule>
  <subcellularLocation>
    <location>Secreted</location>
  </subcellularLocation>
</comment>

cofactor

Example: P26662

<feature type="chain" description="Serine protease NS3"
                      id="PRO_0000037644" evidence="4">
  <location>
    <begin position="1027"/>
    <end position="1657"/>
  </location>
</feature>
<feature type="chain" description="Non-structural protein 4A"
                      id="PRO_0000037645" evidence="4">
  <location>
    <begin position="1658"/>
    <end position="1711"/>
  </location>
</feature>

<comment type="cofactor">
  <molecule>Serine protease NS3</molecule>
  <cofactor evidence="14">
    <name>Zn(2+)</name>
    <dbReference type="ChEBI" id="CHEBI:29105"/>
  </cofactor>
  <text evidence="14">Binds 1 zinc ion.</text>
</comment>
<comment type="cofactor">
  <molecule>Non-structural protein 5A</molecule>
  <cofactor evidence="3">
    <name>Zn(2+)</name>
    <dbReference type="ChEBI" id="CHEBI:29105"/>
  </cofactor>
  <text evidence="3">Binds 1 zinc ion in the NS5A N-terminal domain.</text>
</comment>

featureType

The featureType has a mandatory location element of locationType to describe the sequence coordinates of an annotation.

Example: P84077

<feature type="initiator methionine" description="Removed" evidence="6 7 21 22">
  <location>
    <position position="1"/>
  </location>
</feature>
<feature type="chain" description="ADP-ribosylation factor 1" id="PRO_0000207378">
  <location>
    <begin position="2"/>
    <end position="181"/>
  </location>
</feature>
...
<feature type="nucleotide phosphate-binding region" description="GTP" evidence="1 2 3 4 25">
  <location>
    <begin position="126"/>
    <end position="129"/>
  </location>
</feature>
...
<feature type="sequence variant" description="In PVNH8; decreased interaction with GGA3; dbSNP:rs879036238." id="VAR_081272" evidence="23">
  <original>Y</original>
  <variation>H</variation>
  <location>
    <position position="35"/>
  </location>
</feature>
...
<feature type="helix" evidence="1">
  <location>
    <begin position="6"/>
    <end position="9"/>
  </location>
</feature>

The locationType has an optional sequence attribute that is only set (to an isoform ID) when the coordinates are not for the canonical sequence.

Example: P12821

Previous representation:

<comment type="alternative products">
  ...
  <isoform>
    <id>P12821-3</id>
    <id>P22966-1</id>
    <name>Testis-specific</name>
    <name>ACE-T</name>
    <sequence type="described" ref="VSP_035120 VSP_035121"/>
    <text>Variant in position: 32:S->P (in dbSNP:rs4317). Variant in position: 49:S->G (in dbSNP:rs4318).</text>
  </isoform>
  ...
</comment>
...
<feature type="sequence variant" description="In dbSNP:rs13306087." id="VAR_029139">
  <original>A</original>
  <variation>T</variation>
  <location>
    <position position="154"/>
  </location>
</feature>

New representation:

<comment type="alternative products">
  ...
  <isoform>
    <id>P12821-3</id>
    <id>P22966-1</id>
    <name>Testis-specific</name>
    <name>ACE-T</name>
    <sequence type="described" ref="VSP_035120 VSP_035121"/>
  </isoform>
  ...
</comment>
...
<feature type="sequence variant" description="In dbSNP:rs13306087." id="VAR_029139">
  <original>A</original>
  <variation>T</variation>
  <location>
    <position position="154"/>
  </location>
</feature>
...
<feature type="sequence variant" description="In dbSNP:rs4317." id="VAR_x">
  <original>S</original>
  <variation>P</variation>
  <location sequence="P12821-3">
    <position position="32"/>
  </location>
</feature>
<feature type="sequence variant" description="In dbSNP:rs4318." id="VAR_y">
  <original>S</original>
  <variation>G</variation>
  <location sequence="P12821-3">
    <position position="49"/>
  </location>
</feature>

RDF format

The UniProt RDF schema ontology already allowed to describe the product to which an annotation applies and required no changes for this purpose.

The RDF format has a single hierarchy of Annotation classes with various intermediary classes. The subclass Sequence_Annotation groups all classes that refer to a location on a protein sequence. This location is represented with FALDO and always indicates the FALDO reference sequence for the location (the RDF format makes no special case for a canonical sequence). Annotations that do not refer to a specific location on a protein sequence, but that apply to a given product, describe the sequence of this product with a sequence property. The object of this property may be a Sequence or a Chain_Annotation / Peptide_Annotation that describes a sequence that is the product of proteolytic processing.

Please note that the change of mass spectrometry annotations required an adaptation of the hierarchy of Annotation classes: The Mass_Spectrometry_Annotation class no longer is an rdfs:subClassOf of the Sequence_Annotation class, but a direct rdfs:subClassOf of the Annotation class.

Example: Q13421

@prefix up: <http://purl.uniprot.org/core/> .
@prefix uniprot: <http://purl.uniprot.org/uniprot/> .
@prefix isoform: <http://purl.uniprot.org/isoforms/> .
@prefix annotation: <http://purl.uniprot.org/annotation/> .
@prefix faldo: <http://biohackathon.org/resource/faldo#> .

uniprot:Q13421
  up:annotation
    annotation:PRO_0000253560 ,
    <Q13421#SIPADAC7D651EFC09CC> ,
    <Q13421#SIP307BEB951103B073> ,
    <Q13421#SIPB6746E472B99B031> ,
    ...
  up:sequence
    isoform:Q13421-1 ,
    isoform:Q13421-3 ,
    isoform:Q13421-2 ,
    isoform:Q13421-4 ;

annotation:PRO_0000253560
  rdf:type up:Chain_Annotation ;
  rdfs:comment "Megakaryocyte-potentiating factor" ;
  up:range range:22853569102360878tt37tt286 .
range:22853569102360878tt37tt286
  rdf:type faldo:Region ;
  faldo:begin position:22853569102360878tt37 ;
  faldo:end position:22853569102360878tt286 .
position:22853569102360878tt37
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 37 ;
  faldo:reference isoform:Q13421-1 .
position:22853569102360878tt286
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 286 ;
  faldo:reference isoform:Q13421-1 .

<Q13421#SIPADAC7D651EFC09CC>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIP04927440DF8EB941> ,
               <Q13421#SIP727DF431EB6C89EC> .

<Q13421#SIP307BEB951103B073>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIPD59D33F5047A94FD> ;
  up:sequence annotation:PRO_0000253560 .

<Q13421#SIPB6746E472B99B031>
  rdf:type up:Subcellular_Location_Annotation ;
  up:locatedIn <Q13421#SIPD59D33F5047A94FD> ;
  up:sequence isoform:Q13421-2 .

isoform:Q13421-1
  rdf:type up:Simple_Sequence ;
  up:modified "2006-10-17"^^xsd:date ;
  up:version 2 ;
  up:precursor true ;
  up:mass 68986 ;
  up:crc64Checksum "FA17E3609B6CC9CA"^^xsd:token ;
  up:name "1" ;
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" .
isoform:Q13421-3
  rdf:type up:Modified_Sequence ;
  up:name "2" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021059 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" ;
isoform:Q13421-2
  rdf:type up:Modified_Sequence ;
  up:name "3" , "SMRP" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021059 , annotation:VSP_021060 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LRAPLPC" ;
isoform:Q13421-4
  rdf:type up:Modified_Sequence ;
  up:name "4" ;
  up:basedOn isoform:Q13421-1 ;
  up:modification annotation:VSP_021058 , annotation:VSP_021059 .
  rdf:value "MALPTARPLLGSCGTPALGSLLFLLFSL ... LLASTLA" ;

Cross-references to RNAct

Cross-references have been added to RNAct, a database of protein-RNA interaction predictions for model organisms with supporting experimental data.

RNAct is available at https://rnact.crg.eu.

The format of the explicit links is:

Resource abbreviation	RNAct
Resource identifier	UniProtKB accession number
Optional information 1	Molecule type

Example: Q9Y2I1

Show all entries having a cross-reference to RNAct.

Text format

Example: Q9Y2I1

DR   RNAct; Q9Y2I1; protein.

XML format

Example: Q9Y2I1

<dbReference type="RNAct" id="Q9Y2I1">
   <property type="molecule type" value="protein"/>
</dbreference>

RDF format

Example: Q9Y2I1

uniprot:Q9Y2I1
  rdfs:seeAlso <http://purl.uniprot.org/rnact/Q9Y2I1> .
<http://purl.uniprot.org/rnact/Q9Y2I1>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/RNAct> ;
  rdfs:comment "protein" .

Change of the cross-references to Pharos

We have introduced an additional field in the cross-references to the Pharos database to indicate the development status of a target. Targets are categorized into four development/druggability levels (TDLs), ranging from Tclin for approved drugs with known mechanisms of action, to Tdark for targets about which virtually nothing is known.

Text format

Example: P33151

DR   Pharos; P33151; Tbio.

XML format

Example: P33151

<dbReference type="Pharos" id="P33151">
  <property type="development level" value="Tbio"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: P33151

uniprot:P33151
  rdfs:seeAlso <http://purl.uniprot.org/pharos/P33151> .
<http://purl.uniprot.org/pharos/P33151>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Pharos> ;
  rdfs:comment "Tbio" .

Removal of the cross-references to PMAP-CutDB

Cross-references to PMAP-CutDB have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Congenital disorder of glycosylation 1CC
• Epilepsy, idiopathic generalized 16
• Epileptic encephalopathy, early infantile, 78
• Epileptic encephalopathy, early infantile, 79
• Epileptic encephalopathy, early infantile, 80
• Glycosylphosphatidylinositol biosynthesis defect 21
• Hypothyroidism, congenital, non-goitrous, 7
• Hypothyroidism, congenital, non-goitrous, 8
• Hypothyroidism, congenital, non-goitrous, 9
• Intellectual developmental disorder 60 with seizures
• Mental retardation, X-linked, syndromic, 36
• Mitochondrial DNA depletion syndrome 17
• Myopathy, congenital, progressive, with scoliosis
• Nephrotic syndrome 21
• Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly
• Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies
• Neurodevelopmental disorder with cerebellar hypoplasia and spasticity
• Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
• Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies
• Spastic tetraplegia and axial hypotonia, progressive

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• 6-(S-cysteinyl)-8alpha-(pros-histidyl)-FAD (Cys-His)

Changes to keywords

Deleted keyword:

• Complete proteome

Proteomes changes

The UniProt Proteomes portal is offering protein sequence sets obtained from the translation of sequenced genomes. Published genomes from NCBI Genome used to be brought into UniProt if they satisfied the following criteria:

• The genome is annotated and a set of coding sequences is available.
• The number of predicted coding sequences falls within a statistically significant range of published proteomes from neighbouring species.

We have changed these criteria to publish all proteomes that can be derived from NCBI genomes that are not considered to be low quality assemblies. We now use a subset of the RefSeq reasons to exclude a genome assembly to determine which proteomes to bring into UniProtKB and we give the reason(s) why a proteome is excluded from UniProtKB. We also provide two metrics to help users to assess the quality of a proteome:

• A score obtained with the BUSCO software.
• A score based on the number of coding sequences expected based on neighbouring species, "Complete Proteome Detector (CPD)".

The "Complete proteome" keyword was removed from all UniProtKB entries. Individual proteomes can be retrieved from the UniProt website by their unique proteome identifier, e.g. UP000005640.

Headline

A scorpion venom toxin may help unravel the mystery of chronic pain

The old saying goes 'an ounce of prevention is worth a pound of cure', and indeed, our body has developed various strategies to alert us of potential dangers to avoid. One contributor to this strategy is TRPA1, also called the 'wasabi receptor'. TRPA1, a member of the transient receptor family (TRP), is a plasma membrane cation channel expressed by primary afferent sensory neurons. It is activated by chemically reactive electrophiles present in a range of environmental irritants and endogenous inflammatory agents. Cigarette smoke, for example, is rich in reactive electrophiles that can trigger TRPA1 in the cells that line the airways, inducing coughing and sustained airway inflammation. Some plants, such as mustard, wasabi or onions, have evolved compounds that activate TRPA1, possibly to ward off animals that might otherwise eat them. In this context, TRPA1 activation is responsible for the sinus-jolting sting of wasabi and the flood of tears associated with chopping onions.

Not only plants produce TRPA1 activating compounds. Black rock scorpions do too, as has been reported in a recent publication by Lin King et al. This comes as a surprise. Most animal toxins identified so far target voltage-gated ion channels, and the few known to act on TRP channels all activate the capsaicin receptor, TRPV1. The newly discovered black rock scorpion toxin has been called Wasabi receptor toxin or WaTx. In its mature form, it is a 19 amino acid-long peptide, which has the amazing ability to penetrate cells by passive diffusion. This property is not unique to WaTx, other proteins, such as HIV Tat or Drosophila penetratin also share it, but WaTx does not have any sequence similarity to them.

Once in the cell, WaTx binds TRPA1 at the same site as plant and environmental irritants, but the similarity ends there. Reactive electrophiles covalently bind TRPA1 and produce a large increase in the probability of channel opening characterized by brief transitions between open and closed states. This results in the influx of sodium and calcium ions. The influx of Ca(2+), in turn, causes the exocytosis of dense-core vesicles, the release of calcitonin-gene-related peptide (CGRP) and substance P, and ultimately induces neurogenic inflammation. WaTx non-covalent binding to TRPA1 stabilizes the open state of the channel and prolongs open time. Consequently, it induces neuronal depolarization and subsequent hypersensitivities, which are characteristic of chronic pain. In addition, it decreases the relative Ca(2+)-permeability of the channel. The Ca(+2) influx is not sufficient to trigger CGRP release and does not cause any inflammation. These observations show a striking convergent evolution between plants and animals in terms of binding site, resulting, however, in a very different modulation of cation channel activity and a distinct outcome in terms of inflammation.

TRPA1 is expressed in virtually every animal, from worms and humans, but WaTx only activates mammalian orthologs. Why so? It is difficult to say. Black rock scorpions feed on insects like cockroaches and beetles, as well as other small invertebrates such as millipedes, centipedes, spiders and rarely earthworms, but never mammals. Therefore, WaTx may have a deterrent role aimed specifically at mammalian predators.

One thing is certain: with WaTx, scorpions provide us with a powerful tool to study the central neural pathways contributing to chronic pain and to investigate the link between chronic pain and inflammation. TRPA1 is emerging as a potential target for new classes of non-opioid analgesics to treat chronic pain.

As of this release, WaTx has been annotated and is painlessly available in UniProtKB/Swiss-Prot.

UniProtKB news

Removal of the cross-references to EcoGene

Cross-references to EcoGene have been removed.

Change of the cross-references to DisProt

Cross-references to DisProt may now be isoform-specific. The general format of isoform-specific cross-references was described in release 2014_03.

Example: Q9NQC3

Changes to the controlled vocabulary of human diseases

New diseases:

• Deafness, autosomal dominant, 37
• Ectodermal dysplasia 15, hypohidrotic/hair type
• Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp
• Epileptic encephalopathy, early infantile, 77
• Erythrokeratodermia variabilis et progressiva 6
• Hepatitis, fulminant viral
• Hyper-IgE recurrent infection syndrome 4, autosomal recessive
• Hypoalphalipoproteinemia, primary, 2
• Hypopigmentation, organomegaly, and delayed myelination and development
• Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies
• Immunodeficiency 64
• Microangiopathy and leukoencephalopathy, pontine, autosomal dominant
• Mitochondrial DNA depletion syndrome 16, hepatic type
• Myopathy, congenital, with tremor
• Neurodevelopmental disorder with visual defects and brain anomalies
• Night blindness, congenital stationary, 1I
• Oculoectodermal syndrome
• Oocyte maturation defect 7
• Pseudofolliculitis barbae
• Robinow syndrome, autosomal recessive 2
• Trichothiodystrophy 7, non-photosensitive
• Van Esch-O'Driscoll syndrome

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Neuronal dense core vesicle
• Neuronal dense core vesicle membrane
• Postsynaptic early endosome
• Postsynaptic early endosome membrane
• Postsynaptic endocytic zone
• Postsynaptic endosome
• Postsynaptic Golgi apparatus
• Postsynaptic recycling endosome
• Postsynaptic recycling endosome membrane
• Presynaptic active zone membrane
• Presynaptic endocytic zone
• Presynaptic endosome
• Spine apparatus
• Synaptic cell membrane

Headline

Biological weapons in the struggle for life

The apoplast, the extracellular space between plant cells, is a battleground between plants and attacking microorganisms. The battle often starts with the secretion of carbohydrate-degrading enzymes by the invader and a counter-attack by the plant with dedicated enzyme inhibitors. This happens for instance when Phytophthora sojae invades soybean. During very early infection stages (20 minutes to 2 hours), the oomycete expresses and secretes high levels of a xyloglucanase enzyme, called XEG1. XEG1 degrades the plant cell wall polymers and not only permits pathogen invasion, but also provides it with nutrients. XEG1 expression declines rapidly from 3 hours onwards.

Like other plants, soybean monitors the apoplastic environment through pattern recognition receptors and recognizes XEG1 as a PAMP (pathogen-associated molecular pattern). This recognition triggers defense responses, which include the secretion of GIP1, a xyloglucanase inhibitor. Efficient XEG1 inhibition by GIP1 increases soybean resistance towards P. sojae. This could be the end of the story, but P. sojae has another trick up its sleeve.

When Ma et al. studied GIP1 binding to XEG1 paralogs, they retrieved only one protein, called XLP1, in addition to XEG1. Like XEG1, XLP1 is targeted to the apoplast. It also shows a similar expression time course to XEG1, i.e. high levels during very early infection stages, followed by a rapid decline, suggesting a role in virulence. Unlike XEG1, however, XLP1 does not show any xyloglucanase activity. It is 52 residues shorter and is missing one of the residues critical for xyloglucanase activity. XLP1 contributes to P. sojae infectivity, but only in the presence of active XEG1. Thus XLP1 acts as a decoy to disrupt plant defenses. It interacts with GIP1 with a five-fold higher affinity than that of XEG1 and hence neutralizes the GIP1 inhibitor. In this setting, XEG1 can pursue plant cell wall digestion without any hindrance.

The 3 belligerent proteins have been annotated in UniProtKB/Swiss-Prot and are publicly available.

UniProtKB news

Change of annotation topic 'Sequence caution'

The annotation topic Sequence caution reports differences between the protein sequence shown in a UniProtKB entry and other available protein sequences derived from the same gene. It indicates the likely cause for the differences, and when that cause is a frameshift or erroneous termination, the amino acid sequence position(s) of these errors were listed when possible. Since it is nowadays easy to align two protein sequences for comparison, we no longer curate error positions and removed the field where this information was stored.

Text format

We removed the optional Positions field.

Example: P14332

Previous format:

CC   -!- SEQUENCE CAUTION: Sequence=CAA34633.1; Type=Frameshift; Positions=226, 249; Evidence={ECO:0000305};

New format:

CC   -!- SEQUENCE CAUTION: Sequence=CAA34633.1; Type=Frameshift; Evidence={ECO:0000305};

XML format

This change did not affect the UniProtKB XSD.

Example: P14332

Previous format:

<comment type="sequence caution" evidence="3">
  <conflict type="frameshift">
    <sequence resource="EMBL-CDS" id="CAA34633" version="1"/>
  </conflict>
  <location>
    <position position="226"/>
  </location>
  <location>
    <position position="249"/>
  </location>
</comment>

New format:

<comment type="sequence caution" evidence="3">
  <conflict type="frameshift">
    <sequence resource="EMBL-CDS" id="CAA34633" version="1"/>
  </conflict>
</comment>

RDF format

This change required an adaptation of the hierarchy of Annotation classes in the UniProt RDF schema ontology: The Sequence_Caution_Annotation class is no longer an rdfs:subClassOf of the Sequence_Annotation class, but a direct rdfs:subClassOf of the Annotation class.

Example: P14332

Previous format:

uniprot:P14332
  up:annotation <P14332#SIP7159608509D280BB> .

<P14332#SIPBBAF3CC29FCD3715>
  rdf:type up:Frameshift_Annotation ;
  up:conflictingSequence <P14332#SIPD8B2EDFEB46FA203> ;
  up:range range:22572098403906094tt226tt226 ,
           range:22572098403906094tt249tt249 .
range:22572098403906094tt226tt226
  rdf:type faldo:Region ;
  faldo:begin position:22572098403906094tt226 ;
  faldo:end position:22572098403906094tt226 .
position:22572098403906094tt226
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 226 ;
  faldo:reference isoform:P14332-1 .
range:22572098403906094tt249tt249
  rdf:type faldo:Region ;
  faldo:begin position:22572098403906094tt249 ;
  faldo:end position:22572098403906094tt249 .
position:22572098403906094tt249
  rdf:type faldo:Position , faldo:ExactPosition ;
  faldo:position 249 ;
  faldo:reference isoform:P14332-1 .

New format:

uniprot:P14332
  up:annotation <P14332#SIP7159608509D280BB> .

<P14332#SIPBBAF3CC29FCD3715>
  rdf:type up:Frameshift_Annotation ;
  up:conflictingSequence <P14332#SIPD8B2EDFEB46FA203> .

Cross-references to PlantReactome

Cross-references have been added to PlantReactome, a curated resource of core pathways and reactions in plant biology.

PlantReactome is available at https://plantreactome.gramene.org

The format of the explicit links is:

Resource abbreviation	PlantReactome
Resource identifier	Resource identifier
Optional information	Pathway name

Example: P0C128

Show all entries having a cross-reference to PlantReactome.

Text format

Example: P0C128

DR   PlantReactome; R-OSA-5608118; Auxin signalling.

XML format

Example: P0C128

<dbReference type="PlantReactome" id="R-OSA-5608118">
  <property type="pathway name" value="Auxin signalling"/>
</dbReference>

RDF format

Example: P0C128

uniprot:P0C128
  rdfs:seeAlso <http://purl.uniprot.org/plantreactome/R-OSA-5608118> .
<http://purl.uniprot.org/plantreactome/R-OSA-5608118>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/PlantReactome> ;
  rdfs:comment "Auxin signalling" .

Change of the cross-references to Reactome

Cross-references to Reactome may now be isoform-specific. The general format of isoform-specific cross-references was described in release 2014_03.

Example: P00167

Changes to the controlled vocabulary of human diseases

New diseases:

• Aortic valve disease 3
• Arthrogryposis multiplex congenita, myogenic type
• Cerebellar atrophy with seizures and variable developmental delay
• Coffin-Siris syndrome 10
• Congenital hypotonia, epilepsy, developmental delay, and digital anomalies
• Contractures, pterygia, and variable skeletal fusions syndrome 1A
• GIST-plus syndrome
• Holoprosencephaly 12 with or without pancreatic agenesis
• Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities
• Immunodeficiency 63 with lymphoproliferation and autoimmunity
• Intellectual developmental disorder, autosomal recessive 71
• Intellectual developmental disorder 59
• Leber congenital amaurosis 19
• Nephrotic syndrome 20
• Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
• Neurodevelopmental disorder with microcephaly and structural brain anomalies
• Neurodevelopmental disorder with seizures and non-epileptic hyperkinetic movements
• Neuropathy, hereditary motor and sensory, 6C, with optic atrophy
• Noonan syndrome 11
• O'Donnell-Luria-Rodan syndrome
• Polydactyly, postaxial, A10
• Shukla-Vernon syndrome
• Spondyloepimetaphyseal dysplasia, sponastrime type

Modified diseases:

• Arthrogryposis, distal, 2B -> Arthrogryposis, distal, 2B1
• Arthrogryposis, distal, 9 -> Contractural arachnodactyly, congenital
• Hyperlipidemia, familial combined -> Hyperlipidemia, familial combined, 3
• Hyperlipidemia combined 1 -> Hyperlipidemia, familial combined, 1
• Kahn-Kahn-Katsanis syndrome -> Khan-Khan-Katsanis syndrome
• Lipoprotein lipase deficiency -> Hyperlipoproteinemia 1
• Mental retardation, X-linked, syndromic, with hypotonic facies 1 -> Mental retardation-hypotonic facies syndrome, X-linked, 1
• Mental retardation, X-linked, ARX-related -> Mental retardation, X-linked, with or without seizures, ARX-related
• Polydactyly preaxial 4 -> Polydactyly, preaxial 4
• Spastic paraplegia 23 -> Spastic paraplegia 23, autosomal recessive

Deleted diseases

• Mental retardation, X-linked 17

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Cross-link' ('CROSSLNK' in the flat file):

• N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Arg-Cys) (interchain with C-...)
• N5-[4-(S-L-cysteinyl)-5-methyl-1H-imidazol-2-yl]-L-ornithine (Cys-Arg) (interchain with R-...)

New term for the feature key 'Glycosylation' ('CARBOHYD' in the flat file):

• N-linked (Glc) (glycation) arginine

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• S-(2-succinyl)cysteine
• N6-carbamoyllysine
• S-(2,3-dicarboxypropyl)cysteine
• S-cGMP-cysteine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Neuron projection
• Postsynapse
• Postsynaptic density membrane
• Presynapse
• Presynaptic active zone
• Synaptic cleft

Headline

Magnetic personalities

Magnetotactic bacteria sense and align to the Earth's magnetic field, swimming north in the Northern Hemisphere and south in the Southern in the presence of oxygen. This amazing ability to sense the Earth's magnetic field is provided by small organelles, called magnetosomes, formed by iron nanocrystals of either magnetite (Fe₃O₄) or greigite (Fe₃S₄) surrounded by a phospholipid bilayer. Generally, magnetosomes form chains that align along the long axis of the cell using a dedicated actin-like cytoskeletal structure.

Source: Frank Mickoleit CC BY-SA 3.0

Magnetosome formation is a complex process, which includes invagination of the cell inner membrane to form vesicles, iron ion uptake, crystal biomineralization and magnetosome chain assembly. It involves a large number of proteins, encoded by genes clustered in an approximately 100 kb magnetosome island. Among all proteins involved in magnetosome formation, one of the single most important is MamB, a probable iron transporter with a role in both vesicle formation and biomineralization. MamB is stabilized by heterodimerization with MamM. Studies in genetically tractable Magnetospirillum magneticum (strain AMB-1) and Magnetospirillum gryphiswaldense (strain MSR) have pinpointed the function of many more proteins. For instance, MamA forms a scaffold to which other proteins attach on the organelle's exterior. MamI aids in magnetite nucleation, while MamH is another probable iron transporter. MamN may control the pH of the magnetosome lumen. 4 redox-active multi-heme proteins are probably involved in correct iron oxidization (MamP, MamT, MamX and MamE), the latter is also a protease necessary for magnetosome protein maturation. There are proteins that positively regulate crystal size (including MamC, MamD MamG, MamF and those that negatively regulate crystal size (Mms36 and Mms48). Finally MamK is an actin-like protein involved in organelle positioning, along with MamJ.

The interest in magnetosomes goes far beyond the understanding of these fascinating bacteria. Magnetosomes may be instrumental for the improvement of magnetic nanoparticle biotechnologies. Purified bacterial magnetosomes represent magnetic nanoparticles with exceptionally well-defined characteristics, owing to the precise control that is exerted during all stages of biogenesis, and several unprecedented properties, such as high crystallinity, strong magnetization, and a uniform distribution of shape and size that cannot be replicated by synthesis using abiotic processes. In the biomedical field, promising results suggest that magnetosomes could be used in medical imaging, targeted drug delivery and tumor hyperthermia. In the context of wastewater treatment, it has been shown that heavy metal ions can be adsorbed onto magnetosome-producing microorganisms and then removed by magnetic separation. In addition, it may also help us learn more about the origin of life and the evolution of membrane-bound eukaryotic organelles.

As of this release nearly 70 magnetosome proteins have been annotated and can be retrieved using the term magnetosome.

UniProtKB news

Cross-references to DrugCentral

Cross-references have been added to DrugCentral, an online drug information resource providing information on active ingredients chemical entities, pharmaceutical products, drug mode of action, indications, pharmacologic action.

DrugCentral is available at http://drugcentral.org.

The format of the explicit links is:

Resource abbreviation	DrugCentral
Resource identifier	UniProtKB accession number

Example: P35372

Show all entries having a cross-reference to DrugCentral.

Text format

Example: P35372

DR   DrugCentral; P35372; -.

XML format

Example: P35372

<dbReference type="DrugCentral" id="P35372"/>

RDF format

Example: P35372

uniprot:P35372
  rdfs:seeAlso <http://purl.uniprot.org/drugcentral/P35372> .
<http://purl.uniprot.org/drugcentral/P35372>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/DrugCentral> .

Cross-references to Pharos

Cross-references have been added to Pharos, a user interface to the knowledge-base for the Druggable Genome (DG), whose goal is to illuminate the uncharacterized and/or poorly annotated portion of the DG, focusing on three of the most commonly drug-targeted protein families: G-protein-coupled receptors (GPCRs), ion channels (ICs) and kinases.

Pharos is available at https://pharos.nih.gov.

The format of the explicit links is:

Resource abbreviation	Pharos
Resource identifier	UniProtKB accession number

Example: Q7Z3E2

Show all entries having a cross-reference to Pharos.

Text format

Example: Q7Z3E2

DR   Pharos; Q7Z3E2; -.

XML format

Example: Q7Z3E2

<dbReference type="Pharos" id="Q7Z3E2"/>

RDF format

Example: Q7Z3E2

uniprot:Q7Z3E2
  rdfs:seeAlso <http://purl.uniprot.org/pharos/Q7Z3E2> .
<http://purl.uniprot.org/pharos/Q7Z3E2>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Pharos> .

Cross-references to MassIVE

Cross-references have been added to MassIVE, a community resource developed by the NIH-funded Center for Computational Mass Spectrometry to promote the global, free exchange of mass spectrometry data and provide a reusable aggregation of community-scale detection of peptides and proteins observations.

MassIVE is available at https://massive.ucsd.edu/.

The format of the explicit links is:

Resource abbreviation	MassIVE
Resource identifier	UniProtKB accession number

Example: Q8IY92

Show all entries having a cross-reference to MassIVE.

Text format

Example: Q8IY92

DR   MassIVE; Q8IY92; -.

XML format

Example: Q8IY92

<dbReference type="MassIVE" id="Q8IY92"/>

RDF format

Example: Q8IY92

uniprot:Q8IY92
  rdfs:seeAlso <http://purl.uniprot.org/massive/Q8IY92> .
<http://purl.uniprot.org/massive/Q8IY92>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/MassIVE> .

Changes to the controlled vocabulary of human diseases

New diseases:

• Abnormal hair, joint laxity, and developmental delay
• Bleeding disorder, platelet-type 22
• Brain abnormalities, neurodegeneration, and dysosteosclerosis
• Calvarial doughnut lesions with bone fragility
• Calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia
• Cerebellar, ocular, craniofacial, and genital syndrome
• Contractures, pterygia, and variable skeletal fusions syndrome 1B
• Deafness, autosomal recessive, 114
• Deafness, autosomal recessive, 115
• Deafness, autosomal recessive, 99
• Developmental delay with or without dysmorphic facies and autism
• Encephalopathy, acute, infection-induced, 9
• Epileptic encephalopathy, early infantile, 76
• Generalized epilepsy with febrile seizures plus 10
• Immunodeficiency 62
• Intellectual developmental disorder with severe speech and ambulation defects
• Kahn-Kahn-Katsanis syndrome
• Keipert syndrome
• Long QT syndrome 8
• Neurodevelopmental disorder with seizures and speech and walking impairment
• Paganini-Miozzo syndrome
• Paragangliomas 6
• Paragangliomas 7
• Uridine-cytidineuria

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Photoreceptor inner segment membrane
• Photoreceptor outer segment membrane

Modified subcellular location:

• Exosome -> Extracellular exosome

UniRef news

Change of UniRef clustering method from CD-HIT to MMseqs2

We have switched the clustering program for UniRef90 and UniRef50 from CD-HIT to MMseqs2 (Steinegger M. and Soeding J., Nat. Commun. 9 (2018)).

The clustering algorithm remains "Greedy Incremental Clustering" with the same parameters (thanks to the MMseqs2 authors for making this available). UniRef100 was not affected.

UniProt XML news

Removal of whitespace characters in the XML amino acid sequence representations

The <sequence> elements of the UniProtKB, UniParc and UniRef XML representations formatted the amino acid sequence for historic reasons with spaces and newlines. These whitespace characters had to be removed before parsing with native XML tools. To avoid this complication we have removed all whitespace characters in the <sequence> elements, so that they contain only IUPAC amino acid codes.

Headline

The enemy of my enemy is my friend

When prey encounters predator, escape is often the best form of defense. Unfortunately this is not an option for plants, who instead have evolved a range of chemical defenses to deter herbivores, such as insects and other arthropods. These chemical defenses include compounds that are toxic to herbivores (direct defense) as well as compounds that attract herbivore predators (indirect defense).

Indirect defense has been extensively studied in maize. Upon foliar damage by lepidopteran larvae, maize releases a complex volatile terpenoid mixture, which attracts parasitic wasps, like Cotesia marginiventris or Cotesia sesamiae. These wasps deposit eggs in the lepidopteran larvae, which leads to an understandable loss of appetite by the lepidopterans, and eventually their death, when the wasp finally emerges from its host. These volatile terpenoids can also 'prime' neighboring plants, causing them to increase the transcription of defense-related genes and respond faster and more vigorously to subsequent herbivore attacks.

The volatile terpenoid mixture produced by maize under lepidopteran attack includes one sesquiterpene of special interest, which is (E)"-beta-caryophyllene":https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:10357. This same sesquiterpene is also produced by roots upon damage by root-feeding pests, such as western corn rootworm (Diabrotica virgifera virgifera). Here it attracts entomopathogenic nematodes, which also live parasitically inside the infected lepidopterans. (E)-beta-caryophyllene is produced by the (E)-beta-caryophyllene synthase encoded by TPS23, which catalyzes the cyclization of farnesyl diphosphate to (E)-beta-caryophyllene. As expected for a gene involved in plant defense, TPS23 gene expression is tightly regulated. Herbivore-induced leaf damage causes increased expression in leaves, but not in roots, while attack by root-feeding pests increases expression in roots, but not in the shoots. TPS23 transcript levels correlate with the production of (E)-beta-caryophyllene and high-level expressing maize lines are more resistant to herbivores than low-level expressing ones.

(E)-beta-caryophyllene is just one of a host of chemical deterrents that plants deploy against herbivores and other pests: the UniProt plant annotation program aims to capture knowledge of the relevant biochemical pathways using Rhea and ChEBI, as well as many other aspects of plant biology too. Find out more about maize TPS23 in the latest updated version of UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to ChEBI in the ptmlist.txt document file

The ptmlist.txt document, which is available by FTP and on the website, describes post-translational modifications (PTMs) annotated in the UniProt knowledgebase. This release sees the addition of optional cross-references from ptmlist.txt to ChEBI (Chemical Entities of Biological Interest), a freely available dictionary of molecular entities focused on small chemical compounds and derivatives, including modified residues.

Example:

ID   (3R)-3-hydroxyarginine
AC   PTM-0476
FT   MOD_RES
..
KW   Hydroxylation.
DR   ChEBI; CHEBI:78294.

This new mapping to ChEBI will facilitate the integration of data on PTMs with knowledge of enzymatic reactions described in UniProt using the Rhea knowledgebase of biochemical reactions (itself built on ChEBI). The following query allows users to find enzymes in UniProtKB that are capable of creating the modified (3R)-3-hydroxyarginine residue (PTM-0476, CHEBI:78294):

annotation:(type:"catalytic activity" chebi:"(3R)-3-hydroxy-L-arginine residue [78294]")

We have currently mapped over 120 of the most common PTMs in UniProtKB to ChEBI and will continue to add new cross-references to ChEBI in forthcoming releases. This mapping of PTMs to ChEBI is part of our ongoing work on the standardization of knowledge of small molecule chemistry in UniProtKB that now covers enzyme cofactors and reactions as well as PTMs, and that will eventually extend to all small molecule protein interactions. We welcome your feedback on these current and future developments.

Retirement of UniProt decoy databases

Based on usage statistics, we decided to retire the UniProt decoy databases from our FTP site. If you wish to generate decoy databases from UniProt FASTA databases, you can use this software.

Please contact us if you have questions about this change.

Cross-references to NIAGADS

Cross-references have been added to the NIAGADS Alzheimer's GenomicsDB. NIAGADS is a searchable annotation resource that provides access to publicly available NIAGADS summary statistics datasets for Alzheimer's Disease (AD) and related neuropathologies.

NIAGADS is available at https://www.niagads.org/genomics/.

The format of the explicit links is:

Resource abbreviation	NIAGADS
Resource identifier	Resource identifier

Example: E9PDY4

Show all entries having a cross-reference to NIAGADS.

Text format

Example: E9PDY4

DR   NIAGADS; ENSG00000203710; -.

XML format

Example: E9PDY4

<dbReference type="NIAGADS" id="ENSG00000203710"/>

RDF format

Example: E9PDY4

uniprot:E9PDY4
  rdfs:seeAlso <http://purl.uniprot.org/niagads/ENSG00000203710> .
<http://purl.uniprot.org/niagads/ENSG00000203710>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/NIAGADS> .

Cross-references to CPTAC

Cross-references have been added to the CPTAC Assay Portal. CPTAC serves as a centralized public repository of "fit-for-purpose" multiplexed quantitative mass spectrometry-based proteomic targeted assays.
CPTAC is available at https://assays.cancer.gov/.

The format of the explicit links is:

Resource abbreviation	CPTAC
Resource identifier	Resource identifier

Example: P04083

Show all entries having a cross-reference to CPTAC.

Text format

Example: P04083

DR  CPTAC; CPTAC-311; -.

XML format

Example: P04083

<dbReference type="CPTAC" id="CPTAC-311"/>

RDF format

Example: P04083

uniprot:P04083
  rdfs:seeAlso <http://purl.uniprot.org/cptac/CPTAC-311> .
<http://purl.uniprot.org/cptac/CPTAC-311>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/CPTAC> .

Removal of the cross-references to H-InvDB

Cross-references to H-InvDB have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis, distal, 2B2
• Arthrogryposis, distal, 2B3
• Arthrogryposis, distal, 2B4
• Cataract 48
• Ciliary dyskinesia, primary, 41
• Deafness, autosomal recessive, 100
• Deafness, autosomal recessive, 113
• Deafness, autosomal recessive, 94
• Developmental delay with variable intellectual impairment and behavioral abnormalities
• Epileptic encephalopathy, early infantile, 75
• Global developmental delay, progressive ataxia, and elevated glutamine
• Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy
• Hydatidiform mole, recurrent, 3
• Hydatidiform mole, recurrent, 4
• Intellectual developmental disorder with short stature and variable skeletal anomalies
• Koolen-De Vries syndrome
• Leukodystrophy, hypomyelinating, 18
• Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression
• Myopathy, congenital, with fast-twitch type II fiber atrophy
• Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
• Neurodevelopmental disorder with impaired speech and hyperkinetic movements
• Neurodevelopmental disorder with or without variable brain abnormalities
• Oculoskeletodental syndrome
• Polydactyly, preaxial 1
• Popov-Chang syndrome
• Spastic ataxia 9, autosomal recessive
• Spastic paraplegia 80, autosomal dominant
• Spermatogenic failure 36
• Spermatogenic failure 37
• Spermatogenic failure 38

Modified diseases:

• Bisphosphoglycerate mutase deficiency -> Erythrocytosis, familial, 8
• Cardiac arrhythmia with increased serum creatine kinase -> Muscular dystrophy, limb-girdle, autosomal recessive 25
• Deafness, autosomal dominant 34, with or without inflammation -> Deafness, autosomal dominant, 34, with or without inflammation
• Deafness, autosomal recessive 32, with or without immotile sperm -> Deafness, autosomal recessive, 32, with or without immotile sperm
• Epileptic encephalopathy, early infantile, 25 -> Epileptic encephalopathy, early infantile, 25, with amelogenesis imperfecta
• Fetal akinesia deformation sequence -> Fetal akinesia deformation sequence 1
• Gaze palsy, familial horizontal, with progressive scoliosis, 2 -> Gaze palsy, familial horizontal, with progressive scoliosis, 2, with impaired intellectual development
• Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy -> Growth retardation, impaired intellectual development, hypotonia, and hepatopathy
• Hereditary myopathy with early respiratory failure -> Myopathy, myofibrillar, 9, with early respiratory failure
• Lymphedema-distichiasis -> Lymphedema-distichiasis syndrome
• Polyarteritis nodosa -> Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome
• Spinal muscular atrophy, lower extremity-predominant 2, autosomal dominant -> Spinal muscular atrophy, lower extremity-predominant 2A, childhood onset, autosomal dominant
• Spinocerebellar ataxia, autosomal recessive, 1 -> Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy -> Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
• Transient neonatal diabetes mellitus 1 -> Diabetes mellitus, transient neonatal, 1

Headline

The three-peptide itch

Just like pain, itch is a signal provided to our brain that something is wrong, or potentially dangerous. Contrary to pain, where our reflex leads to withdraw from danger, an itch leads to scratching, in order to remove the irritating, potentially toxic agent, be it an insect or a chemical. Although itching in response to environmental cues is crucial for survival, chronic itch can be debilitating and severely impact the well-being of affected persons. It is known that itch is relayed from the skin, via the dorsal root ganglion neurons, to the second order neurons in the spinal cord that project to the brain. Several Mas-related G-protein coupled receptors (MRGPRs) have been identified as the primary targets of itch signals, and many of them, including MRGPRX1 (also called MrgprC11 in rodents) and Mrgpra3, are activated by the anti-malarial drug chloroquine.

However, the molecular and neural mechanisms of itch are not well elucidated, which is why the discovery of new tools to identify itch receptors and develop new drugs is extremely valuable. In this context, conotoxins have proven to be a gold mine. Conotoxins are produced by cone snails as part of an envenomation survival strategy for feeding and defense. They are short peptides (usually 10 to 30 amino acid residues), typically with one or more disulfide bonds. Many of them modulate the activity of ion channels and receptors with very high affinity and specificity. They can be highly selective between closely related receptor subtypes, therefore they could meet specific therapeutic needs with a reduced likelihood of side effects due to off-target drug effects.

In mice, the injection of Conus textile venom, but not that of C. geographus induced a scratching reflex, which was accompanied by the activation of 89% of sensory neurons that were also sensitive to chloroquine. Two peptides, CNF-Tx1 and CNF-Tx2, were isolated from C. textile venom gland and tested in vitro for their activity on MRGPRX1. In parallel, the same activity was measured for two additional peptides, CNF-Sr1 and CNF-Sr2, previously identified in C. spurious and one, CNF-Vc1, from C. victoriae. Three of these peptides were able to activate MRGPRX1: CNF-Tx2 activated the human, but not the mouse ortholog, CNF-Sr1 activates only the mouse, but not the human ortholog, and CNF-Vc1 activated both. CNF-Tx2 and CNF-Vc1 were then tested in a humanized mouse transgenic line, which has a knockout of the entire endogenous MRGPR cluster and expresses human MRGPRX1 in primary sensory neurons. In this setting, both peptides elicited a scratching reflex, further confirming that CNF-Tx2 and CNF-Vc1 act via the itch receptor MRGPRX1. Compared with the well-established MrgprX1 agonist chloroquine, CNF-Tx2 and CNF-Vc1 were 600 times and 200 times more potent, respectively.

The 5 conopeptides have been updated in UniProtKB/Swiss-Prot and are publicly available.

UniProt website news

We have changed our BLAST default dataset from UniProtKB to "Reference proteomes + Swiss-Prot". You can still select UniProtKB or other options under "Target database" in the BLAST submission form.

UniProtKB news

Cross-references to ABCD

Cross-references have been added to the ABCD (AntiBodies Chemically Defined) Database, a manually curated depository of sequenced antibodies.

ABCD is available at https://web.expasy.org/abcd.

The format of the explicit links is:

Resource abbreviation	ABCD
Resource identifier	UniProtKB accession number

Example: P07766

Show all entries having a cross-reference to ABCD.

Text format

Example: P07766

DR   ABCD; P07766; -.

XML format

Example: P07766

<dbReference type="ABCD" id="P07766"/>

RDF format

Example: P07766

uniprot:P07766
  rdfs:seeAlso <http://purl.uniprot.org/abcd/P07766> .
<http://purl.uniprot.org/abcd/P07766>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/ABCD> .

Removal of the cross-references to ProDom

Cross-references to ProDom have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Amelogenesis imperfecta 3C
• Brain small vessel disease 3
• Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma
• Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome
• Charcot-Marie-Tooth disease, axonal, 2EE
• Combined oxidative phosphorylation deficiency 38
• Combined oxidative phosphorylation deficiency 39
• Cone-rod dystrophy and hearing loss 2
• Cryptophthalmos, unilateral or bilateral, isolated
• D-lactic aciduria
• Deafness, Y-linked 2
• Dyschromatosis universalis hereditaria 1
• Epilepsy, idiopathic generalized 15
• Epileptic encephalopathy, early infantile, 72
• Epileptic encephalopathy, early infantile, 73
• Epileptic encephalopathy, early infantile, 74
• Facial dysmorphism, hypertrichosis, epilepsy, intellectual and developmental delay, and gingival overgrowth syndrome
• Fetal akinesia deformation sequence 2
• Fetal akinesia deformation sequence 3
• Fetal akinesia deformation sequence 4
• Gastrointestinal ulceration, recurrent, with dysfunctional platelets
• Huriez syndrome
• Immunodeficiency 60
• Immunodeficiency 61
• Intellectual developmental disorder, autosomal recessive 69
• Intellectual developmental disorder, autosomal recessive 70
• Intellectual developmental disorder, X-linked 108
• Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
• Intellectual developmental disorder with short stature, facial anomalies, and speech defects
• Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate
• Microcephaly, growth deficiency, seizures, and brain malformations
• Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy
• Muscular dystrophy, congenital, megaconial type
• Myoclonus, familial, 2
• Neurodevelopmental disorder and language delay with or without structural brain abnormalities
• Neurodevelopmental disorder with central and peripheral motor dysfunction
• Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination
• Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
• Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis
• Spinocerebellar ataxia, autosomal recessive, 27
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3
• Spondyloepimetaphyseal dysplasia with joint laxity, 3
• Spondyloepiphyseal dysplasia, Kondo-Fu type
• T-cell lymphoma, subcutaneous panniculitis-like
• Turnpenny-Fry syndrome
• Witteveen-Kolk syndrome

Modified diseases:

• Acyl-CoA dehydrogenase family, member 9, deficiency -> Mitochondrial complex I deficiency, nuclear type 20
• Alport syndrome, autosomal dominant -> Alport syndrome 3, autosomal dominant
• Alport syndrome, autosomal recessive -> Alport syndrome 2, autosomal recessive
• Alport syndrome, X-linked -> Alport syndrome 1, X-linked
• Bart-Pumphrey syndrome -> Knuckle pads, leukonychia, and sensorineural deafness
• Capillary malformation-arteriovenous malformation -> Capillary malformation-arteriovenous malformation 1
• Congenital disorder of glycosylation with defective fucosylation -> Congenital disorder of glycosylation with defective fucosylation 1
• Dementia Lewy body -> Dementia, Lewy body
• Dopamine beta-hydroxylase deficiency -> Orthostatic hypotension 1
• Ectodermal dysplasia, anhidrotic, with immunodeficiency X-linked -> Ectodermal dysplasia and immunodeficiency 1
• Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency autosomal dominant -> Ectodermal dysplasia and immunodeficiency 2
• Ectodermal dysplasia, Rapp-Hodgkin type -> Rapp-Hodgkin syndrome
• Epidermodysplasia verruciformis -> Epidermodysplasia verruciformis 1
• Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant -> Hyper-IgE recurrent infection syndrome 1, autosomal dominant
• Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive -> Hyper-IgE recurrent infection syndrome 2, autosomal recessive
• Hypomagnesemia, seizures, and mental retardation -> Hypomagnesemia, seizures, and mental retardation 1
• Jansen metaphyseal chondrodysplasia -> Metaphyseal chondrodysplasia, Jansen type
• Lethal arthrogryposis with anterior horn cell disease -> Congenital arthrogryposis with anterior horn cell disease
• Marfan lipodystrophy syndrome -> Marfanoid-progeroid-lipodystrophy syndrome
• Mental retardation, X-linked 49 -> Raynaud-Claes syndrome
• Mental retardation, X-linked 61 -> Tonne-Kalscheuer syndrome
• Neurodevelopmental disorder with brain, liver, and lung abnormalities -> Rajab interstitial lung disease with brain calcifications
• Neuropathy, congenital hypomyelinating or amyelinating -> Neuropathy, congenital hypomyelinating, 1, autosomal recessive
• Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy -> Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
• Popliteal pterygium syndrome, lethal type -> Bartsocas-Papas syndrome
• X-linked hypogammaglobulinemia and isolated growth hormone deficiency -> Growth hormone deficiency, isolated, 3, with agammaglobulinemia

Deleted diseases

• Cardiomyopathy, familial hypertrophic 19
• Myopathy, centronuclear, 3
• Parkes Weber syndrome

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Magnetosome
• Magnetosome lumen
• Magnetosome membrane

Changes to keywords

New keyword:

• Magnetosome

Headline

Love's Labour (nearly) Lost

Actin is a globular multi-functional protein that forms microfilaments. It is probably one of the most abundant proteins in our cells, and in almost all eukaryotic cells. Actin plays crucial roles in many processes essential to life, such as cell migration and division, and muscle contraction. Actin undergoes several post-translational modifications thought to control its cellular functions. Among them is histidine methylation, a rare modification in vertebrates that affects only a few proteins, but which was reported to occur in actin over a half-century ago. Two recent publications revealed the identity of the enzyme catalyzing this methylation, namely a SET domain-containing protein called SETD3. This is not only the first actin methylase, but also the first histidine methylase to be identified in vertebrates.

SETD3 had previously been reported to be a methylase, but a histone methyltransferase, modifying essentially lysine residues. This observation was consistent with the well-established role of SET domain-containing proteins in histone methylation on lysine residues. Consistent, yes, but erroneous! SETD3 actually methylates only actin and only at histidine-73 (His-73). Structural studies showed that the catalytic pocket so perfectly fits the actin peptide, with an extensive network of interactions, that accommodation of divergent sequences may be quite inefficient. From a functional point view, His-73 methylation modestly accelerates the assembly of actin filaments and somewhat reduces the nucleotide-exchange rate on actin monomers. SETD3 knockout mice are viable and overall healthy, in spite of several moderate phenotypes, including some skeletal muscle myopathy, abnormal cardiac electrocardiogram and mildly decreased lean mass. So what? One could think that SETD3-catalyzed histidine methylation of actin is not so important after all, if not for the observation that litter sizes of homozygous knockout females are significantly smaller than litters from wild-type or heterozygous females. This is due to incomplete delivery, with fetuses remaining in utero. The mutant females experience uterus contraction problems that are not improved by oxytocin administration. In vitro SETD3-depleted human myometrial cells also have impeded signal-induced contractions by oxytocin and endothelin-1/EDN1, supporting a role for His-73 methylation in uterine smooth muscle cell contraction during parturition.

The UniProtKB/Swiss-Prot SETD3 entries have been updated and are publicly available as of this release.

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Coffin-Siris syndrome 8
• Galloway-Mowat syndrome 6
• Galloway-Mowat syndrome 7
• Galloway-Mowat syndrome 8
• Microcephaly 25, primary, autosomal recessive
• Neurodevelopmental disorder, X-linked, with craniofacial abnormalities
• Oocyte maturation defect 6
• Retinitis pigmentosa 85

Modified diseases:

• Cone-rod dystrophy and hearing loss -> Cone-rod dystrophy and hearing loss 1
• Hydrops fetalis, non-immune, and/or atrial septal defect -> Lymphatic malformation 7
• Lymphedema, hereditary, 1A -> Lymphatic malformation 1
• Lymphedema, hereditary, 1C -> Lymphatic malformation 3
• Lymphedema, hereditary, 1D -> Lymphatic malformation 4
• Lymphedema, hereditary, 3 -> Lymphatic malformation 6
• Mental retardation, autosomal dominant 19 -> Neurodevelopmental disorder with spastic diplegia and visual defects
• Myoclonus, familial cortical -> Myoclonus, familial, 1
• Neurofibromatosis 1-like syndrome -> Legius syndrome
• Partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome -> Lipodystrophy, familial partial, 7
• Porencephaly 1 -> Brain small vessel disease 1 with or without ocular anomalies
• Porencephaly 2 -> Brain small vessel disease 2

Deleted diseases

• Brain small vessel disease with or without ocular anomalies
• Macrocephaly, macrosomia, facial dysmorphism syndrome.

Headline

A pox on your messenger

Millions of years of coexistence between viruses and their hosts has imposed a selection pressure on hosts to develop the most efficient defense systems possible, while viruses evolve more and more complex strategies to escape them. New findings from James B. Eaglesham and co-workers describe how viruses block second messenger production to evade innate immunity.

The innate immune system is the first line of host defense; it relies on pattern recognition receptors (PRRs) to detect pathogen-specific molecules. The enzyme cyclic 2',3'-cyclic GMP-AMP (cGAMP) synthase cGAS is a PRR that recognizes cytosolic double-stranded DNA, a marker for viral infection, and catalyzes the formation of cGAMP. cGAMP in turn activates STING (also known as TMEM173) and type I interferon and NF-kappa-B responses, leading to a potent anti-viral state. The poxin family of viral proteins cleave cytosolic 2',3'-cGAMP into linear Gp[2'-5']Ap[3'], thereby preventing the activation of STING and the resulting induction of the host immune response. Not surprisingly, poxins are required for efficient viral replication in vivo.

Poxins are found in poxviruses, a large family of DNA viruses infecting mammalian cells, and baculoviruses, which target insect cells. The active site is conserved between poxviruses, including vaccinia virus poxin, and baculoviruses, an amazing observation considering the evolutionary distance between these viral families. Even more surprising is the presence of an enzymatically active poxin homolog in the silk moth Bombyx mori and other moth and butterfly genomes! The current hypothesis for the spread of poxins between insects and insect and mammalian viruses is that poxviruses and baculoviruses can share overlapping host tropisms and readily acquire genes through homologous recombination.

UniProtKB/Swiss-Prot poxin entries have been updated and should not escape your attention.

UniProtKB news

Removal of the cross-references to HOVERGEN

Cross-references to HOVERGEN have been removed.

Removal of the cross-references to ProteinModelPortal

Cross-references to ProteinModelPortal have been removed.

In an attempt to improve access to modelling data, we now add a link to the SWISS-MODEL-Workspace for all entries that are not already cross-referenced to the SWISS-MODEL Repository (SMR). This new link will allow users to start a new homology modelling project.

Removal of the cross-references to UniGene

Cross-references to UniGene have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Basal ganglia calcification, idiopathic, 7, autosomal recessive
• Combined oxidative phosphorylation deficiency 37
• Congenital disorder of glycosylation with defective fucosylation 2
• Diamond-Blackfan anemia 18
• Diamond-Blackfan anemia 19
• Diamond-Blackfan anemia 20
• Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2
• Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis
• Epidermodysplasia verruciformis 4
• Epidermodysplasia verruciformis 5
• Epileptic encephalopathy, early infantile, 71
• Global developmental delay with or without impaired intellectual development
• Hypomagnesemia, seizures, and mental retardation 2
• Hypoparathyroidism, X-linked
• Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development
• Intellectual developmental disorder with cardiac defects and dysmorphic facies
• Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
• Lissencephaly 9 with complex brainstem malformation
• Macrocephaly, acquired, with impaired intellectual development
• Menke-Hennekam syndrome 1
• Menke-Hennekam syndrome 2
• Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum
• Mucocutaneous ulceration, chronic
• Myasthenic syndrome, congenital, 25, presynaptic
• Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia
• Odontochondrodysplasia
• Omodysplasia 2
• Spermatogenic failure 35
• Spinal muscular atrophy, lower extremity-predominant, 2B, prenatal onset, autosomal dominant
• Warburg-Cinotti syndrome
• Wiedemann-Rautenstrauch syndrome

Changes to keywords

New keywords:

• Immunoglobulin
• T cell receptor

Deleted keywords:

• Immunoglobulin C region
• Immunoglobulin V region

Headline

A drug arsenal from lupins

Digging into traditional medicines to find new drugs is a proven and fruitful strategy. Think of forskolin, a very effective activator of adenylate cyclase, used daily in numerous laboratories. This agent is produced by the Ayurvedic herb Plectranthus barbatus, which used to be recommended, among others, to treat cardiovascular disorders. Or the anticancer drug paclitaxel (taxol), isolated from Taxus brevifolia, the Pacific yew. Or artemisinin, the most efficient treatment against malaria, which derives from Artemisia annua, also called sweet wormwood, a herb employed in Chinese traditional medicine. Plant metabolites and direct derivatives thereof constitute more than a third of currently approved pharmaceuticals. Lupin seeds also belong to the traditional pharmacopoeia on all continents where it has been cultivated. The great Persian physician Avicenna recommended lupin seed flour, mixed with fenugreek and zedoary, to treat diabetes, as he noticed that this mixture considerably decreased sugar excretion in patients. A thousand years after his observation, the lupin protein mediating this effect, gamma-conglutin, has been identified.

In the lupin seed, most conglutins are storage proteins, which are hydrolyzed during germination and nourish the early stages of seedling growth. By contrast, gamma-conglutin is resistant to proteolysis. In this context, its physiological role in the seed is puzzling, but we have a little more insight into its effect on mammalian cells and organisms. Magni et al. reported that hyperglycemic rats experienced a substantial normalization of blood glucose levels after oral administration of white lupin (Lupinus albus) gamma-conglutin. The decrease in sugar blood level was comparable to that obtained with metformin, a well-established medication for the treatment of type 2 diabetes. This observation was later confirmed and extended to small groups of human volunteers.

After ingestion, gamma-conglutin is not digested in the gastrointestinal tract and the intact protein may be translocated across the intestinal barrier through transcytosis. Once in the blood, it may act at several levels. It seems to bind insulin and may potentiate its activity. When myocytes are incubated with gamma-conglutin, they activate signaling pathways similar to those of insulin, including the activation of the insulin receptor substrate 1 (IRS1), AKT1, and EIF4EBP1/PHAS1. Gamma-conglutin peptides produced in vitro can also inhibit dipeptidyl peptidase-4 (DPP4), an enzyme which degrades incretins, a group of metabolic hormones that stimulate a decrease in blood glucose levels. Gamma-conglutin also enhances the cell surface expression of glucose transporters, including SLC2A4 (GLUT4), and inhibits gluconeogenesis in hepatocytes.

More investigations are needed before gamma-conglutin becomes a drug for type 2 diabetes, but in view of the dynamics of the diabetes epidemic, it seems that nature may be giving us a hand in new drug development.

It's time now for you to enjoy a lupin bean snack and consult our newly annotated UniProtKB/Swiss-Prot lupin gamma-conglutin entries.

UniProt website news

Search for small molecules via InChiKey

We have recently enhanced enzyme annotation in UniProtKB using Rhea, a comprehensive expert-curated knowledgebase of biochemical reactions that uses the ChEBI (Chemical Entities of Biological Interest) ontology to describe reaction participants, their chemical structures, and chemical transformations. We also use ChEBI to annotate enzyme cofactors in UniProtKB.

You can now search UniProtKB for small molecule reaction participants and cofactors using the InChIKey, a standard hashed representation of the IUPAC International Chemical Identifier (InChI) that provides a unique and compact representation of chemical structure data. The UniProt website supports flexible chemical structure searches with the complete InChIKey, as well as with the connectivity and stereochemistry layers, or the connectivity layer alone. You can search our "Catalytic activity" or "Cofactor" annotations, or both combined, by using the new "Small molecule" advanced search field:

This new InChIKey-based search will help unlock the power of chemical structure data in UniProtKB, particularly when combined with our existing search tools and options for biological data. It complements the chemical ontology search, which allows users to search UniProtKB for chemical classes of biological interest like lipids, amino acids, sugars and specializations thereof, using identifiers from the ChEBI ontology of small molecules.

See How can I search UniProt for chemical or reaction data?

UniProtKB news

Changes to the controlled vocabulary of human diseases

New diseases:

• Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development
• Baker-Gordon syndrome
• Cardiac-urogenital syndrome
• Charcot-Marie-Tooth disease, demyelinating, 1G
• Ciliary dyskinesia, primary, 39
• Ciliary dyskinesia, primary, 40
• Congenital anomalies of kidney and urinary tract 3
• Deafness, autosomal recessive, 112
• Epidermodysplasia verruciformis 2
• Epidermodysplasia verruciformis 3
• Epileptic encephalopathy, early infantile, 69
• Epileptic encephalopathy, early infantile, 70
• Fibrosis, neurodegeneration, and cerebral angiomatosis
• Global developmental delay, lung cysts, overgrowth, and Wilms tumor
• Hyper-IgE recurrent infection syndrome 3, autosomal recessive
• Hypotrichosis 14
• Immunodeficiency 59 and hypoglycemia
• Inflammatory bowel disease, immunodeficiency, and encephalopathy
• Intellectual developmental disorder, autosomal recessive 67
• Intellectual developmental disorder, autosomal recessive 68
• Intellectual developmental disorder with autism and speech delay
• Lymphoproliferative syndrome 3
• Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations
• Mental retardation, autosomal recessive 66
• Mirror movements 4
• Mitochondrial complex I deficiency, nuclear type 2
• Mitochondrial complex I deficiency, nuclear type 3
• Mitochondrial complex I deficiency, nuclear type 4
• Mitochondrial complex I deficiency, nuclear type 5
• Mitochondrial complex I deficiency, nuclear type 6
• Mitochondrial complex I deficiency, nuclear type 7
• Mitochondrial complex I deficiency, nuclear type 8
• Mitochondrial complex I deficiency, nuclear type 9
• Mitochondrial complex I deficiency, nuclear type 10
• Mitochondrial complex I deficiency, nuclear type 11
• Mitochondrial complex I deficiency, nuclear type 12
• Mitochondrial complex I deficiency, nuclear type 13
• Mitochondrial complex I deficiency, nuclear type 14
• Mitochondrial complex I deficiency, nuclear type 15
• Mitochondrial complex I deficiency, nuclear type 16
• Mitochondrial complex I deficiency, nuclear type 17
• Mitochondrial complex I deficiency, nuclear type 18
• Mitochondrial complex I deficiency, nuclear type 19
• Mitochondrial complex I deficiency, nuclear type 21
• Mitochondrial complex I deficiency, nuclear type 22
• Mitochondrial complex I deficiency, nuclear type 23
• Mitochondrial complex I deficiency, nuclear type 24
• Mitochondrial complex I deficiency, nuclear type 25
• Mitochondrial complex I deficiency, nuclear type 26
• Mitochondrial complex I deficiency, nuclear type 27
• Mitochondrial complex I deficiency, nuclear type 28
• Mitochondrial complex I deficiency, nuclear type 29
• Mitochondrial complex I deficiency, nuclear type 30
• Mitochondrial complex I deficiency, nuclear type 31
• Mitochondrial complex I deficiency, nuclear type 32
• Mitochondrial complex I deficiency, nuclear type 33
• Mitochondrial complex I deficiency, mitochondrial type 1
• Neurodegeneration, childhood-onset, with cerebellar atrophy
• Noonan syndrome 2
• Polydactyly, postaxial, A9
• Pontocerebellar hypoplasia 12
• RHYNS syndrome
• Snijders Blok-Campeau syndrome
• Trichohepatoneurodevelopmental syndrome
• Vertebral anomalies and variable endocrine and T-cell dysfunction
• Visual impairment and progressive phthisis bulbi

Modified disease:

• Mitochondrial complex I deficiency -> Mitochondrial complex I deficiency, nuclear type 1

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• (Z)-2,3-didehydroaspartate

Headline

Let's twist again with Myo1D

At first glance, we look bilaterally symmetrical. Our left side appears pretty much the mirror image of the right one. For our internal organs, it's a completely different story. For instance, our heart is on the left of our body, while the liver lies to the right. Macroscopic left-right patterning is only one aspect of an organism's asymmetry. Actually all known life forms show asymmetric properties in chemical structures, as well as in macroscopic anatomy, development and behavior. However, not much is known about the nature of the link between molecular-level and macroscopic asymmetry.

Studies in Drosophila led to the discovery of a crucial role for an unconventional myosin, called Myo31DF or Myo1D, in left-right asymmetry. Myo1D inactivation in the fly can reverse handedness of the gut and testes. In a recent publication, Lebreton et al. have extended these observations, showing that ectopic expression of Myo1D in 'naive' tissues, i.e. devoid of left-right asymmetry, such as epidermis and trachea, was sufficient to drive laterality. In the larval epidermis, Myo1D expression induced dextral twisting of the whole larval body, which could rotate up to 180°, resulting in abnormal crawling behavior. In the trachea, pronounced right-handed twisting, with a spiraling ribbon shape with multiple turns, was observed instead of the smooth and linear conformation of the wild-type tissue. This asymmetry was also seen at the cellular level. In control conditions, epidermal cells were perpendicular to the anterior-posterior axis. In contrast, cells ectopically expressing Myo1D showed elongation and a clear shift in membrane orientation toward one side. Myo1D functions as an actin-based motor protein with ATPase activity and this activity was required for the establishment of left-right asymmetry. In vitro Myo1D caused actin filaments to move in anticlockwise circular motion, suggesting that the multiscale property of Myo1D emerges from its molecular interaction with F-actin.

Does this conclusion apply to vertebrates? This answer is not straightforward. Experiments in some vertebrates point to a role for MYO1D in left-right patterning. In Xenopus, MYO1D morpholino knockdown affected organ placement in over 50% of the morphant tadpoles. In Zebrafish, MYO1D plays a role in the formation of Kupffer's vesicle, an organ that functions as left-right organizer during embryogenesis. However, in rat, MYO1D knockout didn't lead to visceral situs inversus and caused no obvious motor defects, indicating that, at least in certain mammals, MYO1D is not involved in left-right body asymmetry.

As of this release, UniProtKB/Swiss-Prot MYO1D entries have been updated and are publicly available.

UniProtKB news

Removal of the cross-references to CleanEx

Cross-references to CleanEx have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

• Bone marrow failure syndrome 5
• Capillary malformation-arteriovenous malformation 2
• Cardiac, facial, and digital anomalies with developmental delay
• Cardiomyopathy, dilated 2C
• Cortical dysplasia, complex, with other brain malformations 9
• Deafness, X-linked, 7
• Diarrhea 9
• Diarrhea 10, protein-losing enteropathy type
• Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis
• Epileptic encephalopathy, early infantile, 68
• Erythroleukemia, familial
• Hyperparathyroidism, transient neonatal
• Immunodeficiency 15A
• Intellectual developmental disorder and retinitis pigmentosa
• Microcephaly 24, primary, autosomal recessive
• Myasthenic syndrome, congenital, 23, presynaptic
• Myasthenic syndrome, congenital, 24, presynaptic
• Nephrotic syndrome 17
• Nephrotic syndrome 18
• Nephrotic syndrome 19
• Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
• Neuropathy, congenital hypomyelinating, 2
• Neuropathy, congenital hypomyelinating, 3
• Orthostatic hypotension 2
• Ovarian dysgenesis 8
• Periventricular nodular heterotopia 8
• Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2
• Retinitis pigmentosa 83
• Retinitis pigmentosa 84

Modified diseases:

• Diarrhea 7 -> Diarrhea 7, protein-losing enteropathy type
• Immunodeficiency 15 -> Immunodeficiency 15B

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• ADP-ribosyldiphthamide

RDF news

Change of URIs for Orphanet

For historic reasons, UniProt had to generate URIs to cross-reference databases that did not have an RDF representation. Our policy is to replace these by the URIs generated by the cross-referenced database once it starts to distribute an RDF representation of its data.

The URIs for the Orphanet database have therefore been updated from:

http://purl.uniprot.org/orphanet/<ID>

to:

http://www.orpha.net/ORDO/Orphanet_<ID>

If required for backward compatibility, you can use the following query to add the old URIs:

PREFIX owl:<http://www.w3.org/2002/07/owl#>
PREFIX up:<http://purl.uniprot.org/core/>
INSERT
{
   ?protein rdfs:seeAlso ?old .
   ?old owl:sameAs ?new .
   ?old up:database <http://purl.uniprot.org/database/orphanet> .
}
WHERE
{
   ?protein rdfs:seeAlso ?new .
   ?new up:database <http://purl.uniprot.org/database/Orphanet> .
   BIND(iri(concat('http://purl.uniprot.org/orphanet/', substr(str(?new),32))) AS ?old)
}

The dereferencing of existing http://purl.uniprot.org/orphanet/<ID> URIs will be maintained.

Headline

Engaging and disengaging: CRISPR rings

CRISPR-Cas systems are an RNA-guided adaptive immune response that bacteria and archaea use to defend against invasive genetic elements of bacterial (plasmid) or viral origin. Pieces of foreign DNA incorporated into CRISPR arrays provide a "memory" of having encountered the invader. These arrays are transcribed and processed, and the resulting CRISPR RNA (crRNA) is used by the interference complex to recognize the invader if it is re-encountered. Once recognized, foreign nucleic acids are quickly degraded, providing immunity. There are different types of CRISPR-Cas systems, mainly characterized by the presence or absence of certain Cas proteins. For example, the Cas3, Cas9, and Cas10 proteins are hallmarks of the CRISPR/Cas types I, II and III, respectively. The best known system is the type II Cas9-encoding system, which has been coopted by scientists for genome editing. The most intriguing one is the type III system, which has additional, novel control mechanisms not found in the other systems.

The type III interference complex is composed of crRNA, Cas10 and proteins Csm2, Csm3, Csm4 and Csm5. Once the target RNA has bound to the Csm interference complex it is cleaved by the complex, which acts as a sequence-specific endoribonuclease (RNase). There is an additional component to this system: Csm6. Under basal conditions, Csm6 is an inactive RNase and is not part of the Csm complex, however its presence is required for full CRISPR-Cas immunity where it non-specifically degrades invader-derived RNA transcripts. How then is Csm6 RNase activity turned on and, once activated, how is it turned off, considering that an uncontrolled RNase activity could be detrimental to the cell? The answer to these questions has been revealed in recent publications. Homodimeric Csm6 is activated by cyclic oligoadenylates (cOA), ring-shaped second messengers synthesized by the C-terminal GGDEF (also called Palm) domain of Cas10. Binding of cOA to the Csm6 dimer interface pocket formed by its CARF (CRISPR-associated Rossman fold) domains allosterically regulates its RNase activity. The type of cyclic oligoadenylates produced is species-specific. Streptococcus thermophilus and Enterococcus italicus make cyclic hexaadenylate (cA₆), while Csm6 of Thermus thermophilus is stimulated by cyclic tetraadenylate (cA₄), suggesting Cas10 in this organism synthesizes cA₄. As the target RNA associated with the CRISPR complex is degraded, the cOA synthase activity of Cas10 shuts off, halting second messenger synthesis. Additionally, 2 proteins with ring-specific nuclease activity able to degrade cOA have been recently isolated from Saccharolobus solfataricus (formerly called Sulfolobus solfataricus), which would turn down Csm6 activity and prevent uncontrolled degradation of cellular RNA.

As of this release several Cas10 proteins and the ring nucleases of S.solfataricus have been annotated and can be retrieved.

UniProtKB news

Cross-references to jPOST

Cross-references have been added to jPOST, a proteomics database containing re-analysis results with unified criteria for raw data from several ProteomeXchange (PX) repositories.

jPOST is available at https://globe.jpostdb.org/.

The format of the explicit links is:

Resource abbreviation	jPOST
Resource identifier	UniProtKB accession number

Example: Q8IY92

Show all entries having a cross-reference to jPOST.

Text format

Example: Q8IY92

DR   jPOST; Q8IY92; -.

XML format

Example: Q8IY92

<dbReference type="jPOST" id="Q8IY92"/>

RDF format

Example: Q8IY92

uniprot:Q8IY92
  rdfs:seeAlso <http://purl.uniprot.org/jpost/Q8IY92> .
<http://purl.uniprot.org/jpost/Q8IY92>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/jPOST> .

Changes to the controlled vocabulary of human diseases

New diseases:

• CHAND syndrome
• CLAPO syndrome
• Deafness, autosomal dominant, 74
• Deafness, autosomal recessive, 111
• Epileptic encephalopathy, early infantile, 67
• Extraoral halitosis due to methanethiol oxidase deficiency
• Glycosylphosphatidylinositol biosynthesis defect 18
• Growth hormone deficiency, isolated, 4
• Growth hormone deficiency, isolated, 5
• Hennekam lymphangiectasia-lymphedema syndrome 3
• Hypertelorism, Teebi type
• Intellectual developmental disorder with hypertelorism and distinctive facies
• Intellectual developmental disorder with macrocephaly, seizures, and speech delay
• Joubert syndrome 35
• Macrodactyly
• Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome
• Muscular dystrophy, limb-girdle, autosomal recessive 23
• Muscular dystrophy-dystroglycanopathy limb-girdle C8
• Ophthalmoplegia, external, with rib and vertebral anomalies
• Osteochondrodysplasia, brachydactyly, and overlapping malformed digits
• Saul-Wilson syndrome
• Spermatogenic failure 33
• Spermatogenic failure 34
• Spinocerebellar ataxia 48
• Spondyloepimetaphyseal dysplasia, Krakow type
• Squalene synthase deficiency
• Usher syndrome 4

Modified diseases:

• Congenital disorder of glycosylation 1O -> Muscular dystrophy-dystroglycanopathy limb-girdle C15
• Liddle syndrome -> Liddle syndrome 1
• Limb-girdle muscular dystrophy 1E -> Muscular dystrophy, limb-girdle, autosomal dominant 1
• Limb-girdle muscular dystrophy 1F -> Muscular dystrophy, limb-girdle, autosomal dominant 2
• Limb-girdle muscular dystrophy 1G -> Muscular dystrophy, limb-girdle, autosomal dominant 3
• Limb-girdle muscular dystrophy 2W -> Muscular dystrophy, autosomal recessive, with cardiomyopathy and triangular tongue
• Limb-girdle muscular dystrophy 2X -> Cardiac arrhythmia with increased serum creatine kinase
• Limb-girdle muscular dystrophy 2Y -> Myopathy, autosomal recessive, with rigid spine and distal joint contractures
• Limb-girdle muscular dystrophy 2Z -> Muscular dystrophy, limb-girdle, autosomal recessive 21
• Limb-girdle muscular dystrophy 2A -> Muscular dystrophy, limb-girdle, autosomal recessive 1
• Limb-girdle muscular dystrophy 2B -> Muscular dystrophy, limb-girdle, autosomal recessive 2
• Limb-girdle muscular dystrophy 2C -> Muscular dystrophy, limb-girdle, autosomal recessive 5
• Limb-girdle muscular dystrophy 2D -> Muscular dystrophy, limb-girdle, autosomal recessive 3
• Limb-girdle muscular dystrophy 2E -> Muscular dystrophy, limb-girdle, autosomal recessive 4
• Limb-girdle muscular dystrophy 2F -> Muscular dystrophy, limb-girdle, autosomal recessive 6
• Limb-girdle muscular dystrophy 2G -> Muscular dystrophy, limb-girdle, autosomal recessive 7
• Limb-girdle muscular dystrophy 2H -> Muscular dystrophy, limb-girdle, autosomal recessive 8
• Limb-girdle muscular dystrophy 2J -> Muscular dystrophy, limb-girdle, autosomal recessive 10
• Limb-girdle muscular dystrophy 2L -> Muscular dystrophy, limb-girdle, autosomal recessive 12
• Limb-girdle muscular dystrophy 2Q -> Muscular dystrophy, limb-girdle, autosomal recessive 17
• Limb-girdle muscular dystrophy 2S -> Muscular dystrophy, limb-girdle, autosomal recessive 18
• Moyamoya disease 6 with achalasia -> Moyamoya disease 6 with or without achalasia
• Myopathy, congenital, with neuropathy and deafness -> Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
• Native American myopathy -> Myopathy, congenital, Bailey-Bloch
• Non-syndromic orofacial cleft 8 -> Orofacial cleft 8
• Retinitis pigmentosa with or without situs inversus -> Retinitis pigmentosa 82 with or without situs inversus

Deleted diseases

• Limb-girdle muscular dystrophy 1A
• Limb-girdle muscular dystrophy 1B
• Limb-girdle muscular dystrophy 1C
• Limb-girdle muscular dystrophy 2R

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• ADP-ribosylglycine
• ADP-ribosyltyrosine

Changes in subcellular location controlled vocabulary

New subcellular locations:

• Host pathogen-containing vacuole
• Host pathogen-containing vacuole lumen
• Host pathogen-containing vacuole membrane
• Host vacuole

Headline

Enhanced enzyme annotation in UniProtKB using Rhea

This release marks a major advance in the way UniProt describes enzyme function, with the introduction of Rhea as a vocabulary to annotate and represent enzyme-catalysed reactions in UniProtKB.

Rhea is a comprehensive expert-curated knowledgebase of biochemical reactions that uses the ChEBI (Chemical Entities of Biological Interest) ontology to describe reaction participants, their chemical structures, and chemical transformations. Rhea provides stable unique identifiers for reactions and standard computationally tractable descriptors for chemical transformations.

The enhanced enzyme annotations created using Rhea will form the basis of new search and identifier mapping services in UniProtKB that combine knowledge of small molecules and proteins. They will help UniProt users to more easily integrate and analyse metabolomic data, annotate metabolic networks and models, or mine reaction data to study enzyme evolution and predict new pathways for drug production or bioremediation.

Recent publications provide additional information on Rhea reactions and examples of services that integrate Rhea with biological knowledge from UniProtKB; we hope these will inspire you to dig deeper into the wealth of enzyme data in UniProtKB.

For further technical details about this change see below.

UniProtKB news

Standardization of 'Catalytic activity' annotations

A 'Catalytic activity' annotation describes a catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes. Up to now, UniProt has followed the recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) for the description of enzymatic activities, except for reactions that are described in the scientific literature, but that are not (yet) covered by the NC-IUBMB. The focus of the NC-IUBMB is the nomenclature and classification of enzymes by the reactions they catalyze. For this purpose the NC-IUBMB typically describes an exemplary reaction for each class of enzymes, with the understanding that individual members of the class may use alternative reactants. The NC-IUBMB use their own names for the reactants. To allow UniProt to curate reactions at the level of specific enzymes instead of enzyme classes, and to use standardized names for reactants, we now use chemical reaction descriptions from the Rhea database whenever possible. Rhea uses the ChEBI (Chemical Entities of Biological Interest) ontology to describe reaction participants that are small molecules as well as the reactive groups of large molecules (such as amino acid residues within proteins). These large molecules are identified by a RHEA-COMP identifier. For catalytic activities that can only be described in the form of free text, we continue to follow the NC-IUBMB descriptions. We have also started to curate the physiological direction of a reaction, i.e. the direction of the net flow of reactants in vivo, where evidence for it is available.

Due to their focus on nomenclature, cross-references to Enzyme Commission (EC) numbers have historically been added to the Protein names subsection of UniProtKB entries. To link the EC numbers to the reactions on which they are based, we now also add them to 'Catalytic activity' annotations.

'Catalytic activity' annotations are found in UniProtKB entries, as well as in UniRule and SAAS annotation rules.

Below is a description of how this change affects the different file formats in which UniProt entries are distributed.

Text format

Note: Regex symbols indicate whether a pattern (as delimited by parentheses) is optional (?) or may occur 1 or more times (+).

Reaction description from Rhea:

CC   -!- CATALYTIC ACTIVITY:
 CC       Reaction=<RheaText>; Xref=<RheaXref>(, <ReactantXref>)+;
 CC        ( EC=<EcNumber>;)?( Evidence={<Evidences>};)?
(CC       PhysiologicalDirection=left-to-right; Xref=<RheaXref>; Evidence={<Evidences>};)?
(CC       PhysiologicalDirection=right-to-left; Xref=<RheaXref>; Evidence={<Evidences>};)?

Where:

• <RheaText>: Textual representation of an undirectional Rhea reaction.
• <RheaXref>: Cross-reference to a Rhea reaction (Rhea:n).
• <ReactantXref>: Cross-reference to a reactant from ChEBI (CHEBI:n) or Rhea (RHEA-COMP:n).
• <EcNumber>: EC number of the corresponding enzyme class, when available.
• <Evidences>: List of evidences, when available.

Example: O36015

Previous format (based on NC-IUBMB):

CC   -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine +
CC       cytidine(32)/guanosine(34) in tRNA = S-adenosyl-L-homocysteine +
CC       2'-O-methylcytidine(32)/2'-O-methylguanosine(34) in tRNA.
CC       {ECO:0000255|HAMAP-Rule:MF_03162}.

New format (based on Rhea):

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cytidine(32)/guanosine(34) in tRNA + 2 S-adenosyl-L-
CC         methionine = 2'-O-methylcytidine(32)/2'-O-methylguanosine(34) in
CC         tRNA + 2 H(+) + 2 S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:42396, Rhea:RHEA-COMP:10246, Rhea:RHEA-
CC         COMP:10247, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856,
CC         ChEBI:CHEBI:59789, ChEBI:CHEBI:74269, ChEBI:CHEBI:74445,
CC         ChEBI:CHEBI:74495, ChEBI:CHEBI:82748; EC=2.1.1.205;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_03162};

Example: A0A0S3QTD0

Previous format (based on NC-IUBMB):

CC   -!- CATALYTIC ACTIVITY: Acetyl-CoA + H(2)O + oxaloacetate = citrate +
CC       CoA. {ECO:0000269|PubMed:29420286}.

New format (based on Rhea):

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=acetyl-CoA + H2O + oxaloacetate = citrate + CoA + H(+);
CC         Xref=Rhea:RHEA:16845, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16452, ChEBI:CHEBI:16947, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57288; EC=2.3.3.16;
CC         Evidence={ECO:0000269|PubMed:29420286};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16846;
CC         Evidence={ECO:0000269|PubMed:29420286};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:16847;
CC         Evidence={ECO:0000269|PubMed:29420286};

Reaction description from NC-IUBMB:

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=<IUBMBText>; EC=<EcNumber>;( Evidence={<Evidences>};)?

Where:

• <IUBMBText>: An NC-IUBMB reaction description.
• <EcNumber>: EC number of the corresponding enzyme class.
• <Evidences>: List of evidences, when available.

Example: P17050

Previous format (based on NC-IUBMB):

CC   -!- CATALYTIC ACTIVITY: Cleavage of non-reducing alpha-(1->3)-N-
CC       acetylgalactosamine residues from human blood group A and AB mucin
CC       glycoproteins, Forssman hapten and blood group A lacto series
CC       glycolipids. {ECO:0000269|PubMed:19683538}.

New format (based on NC-IUBMB):

CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Cleavage of non-reducing alpha-(1->3)-N-
CC         acetylgalactosamine residues from human blood group A and AB
CC         mucin glycoproteins, Forssman hapten and blood group A lacto
CC         series glycolipids.; EC=3.2.1.49;
CC         Evidence={ECO:0000269|PubMed:19683538};

XML format

We have extended the UniProt XSD with new elements and types as shown below in red color:

<xs:complexType name="commentType">
        ...
        <xs:sequence>
            <xs:element name="molecule" type="moleculeType" minOccurs="0"/>
            <xs:choice minOccurs="0">
                ...
                <xs:sequence>
                    <xs:annotation>
                        <xs:documentation>Used in 'catalytic activity' annotations.</xs:documentation>
                    </xs:annotation>
                    <xs:element name="reaction" type="reactionType"/>
                    <xs:element name="physiologicalReaction" type="physiologicalReactionType" minOccurs="0" maxOccurs="2"/>
                </xs:sequence>
                ...
            </xs:choice>
            ...
        </xs:sequence>
        ...
    </xs:complexType>
    ...
    <xs:complexType name="reactionType">
        <xs:annotation>
            <xs:documentation>Describes a chemical reaction.</xs:documentation>
        </xs:annotation>
        <xs:sequence>
            <xs:element name="text" type="xs:string"/>
            <xs:element name="dbReference" type="dbReferenceType" minOccurs="1" maxOccurs="unbounded"/>
        </xs:sequence>
        <xs:attribute name="evidence" type="intListType" use="optional"/>
    </xs:complexType>

    <xs:complexType name="physiologicalReactionType">
        <xs:annotation>
            <xs:documentation>Describes a physiological reaction.</xs:documentation>
        </xs:annotation>
        <xs:sequence>
            <xs:element name="dbReference" type="dbReferenceType"/>
        </xs:sequence>
        <xs:attribute name="direction" use="required">
            <xs:simpleType>
                <xs:restriction base="xs:string">
                    <xs:enumeration value="left-to-right"/>
                    <xs:enumeration value="right-to-left"/>
                </xs:restriction>
            </xs:simpleType>
        </xs:attribute>
        <xs:attribute name="evidence" type="intListType" use="optional"/>
    </xs:complexType>

Reaction description from Rhea:

Example: O36015

Previous format (based on NC-IUBMB):

<comment type="catalytic activity">
  <text evidence="1">S-adenosyl-L-methionine + cytidine(32)/guanosine(34) in tRNA = S-adenosyl-L-homocysteine + 2'-O-methylcytidine(32)/2'-O-methylguanosine(34) in tRNA.</text>
</comment>

New format (based on Rhea):

<comment type="catalytic activity">
  <reaction evidence="1">
    <text>cytidine(32)/guanosine(34) in tRNA + 2 S-adenosyl-L-methionine = 2'-O-methylcytidine(32)/2'-O-methylguanosine(34) in tRNA + 2 H(+) + 2 S-adenosyl-L-homocysteine</text>
    <dbReference type="Rhea" id="RHEA:42396"/>
    <dbReference type="Rhea" id="RHEA-COMP:10246"/>
    <dbReference type="Rhea" id="RHEA-COMP:10247"/>
    <dbReference type="ChEBI" id="CHEBI:15378"/>
    <dbReference type="ChEBI" id="CHEBI:57856"/>
    <dbReference type="ChEBI" id="CHEBI:59789"/>
    <dbReference type="ChEBI" id="CHEBI:74269"/>
    <dbReference type="ChEBI" id="CHEBI:74445"/>
    <dbReference type="ChEBI" id="CHEBI:74495"/>
    <dbReference type="ChEBI" id="CHEBI:82748"/>
    <dbReference type="EC" id="2.1.1.205"/>
  </reaction>
</comment>

Example: A0A0S3QTD0

Previous format (based on NC-IUBMB):

<comment type="catalytic activity">
  <text evidence="2">Acetyl-CoA + H(2)O + oxaloacetate = citrate + CoA.</text>
</comment>

New format (based on Rhea):

<comment type="catalytic activity">
  <reaction evidence="2">
    <text>acetyl-CoA + H2O + oxaloacetate = citrate + CoA + H(+)</text>
    <dbReference type="Rhea" id="RHEA:16845"/>
    <dbReference type="ChEBI" id="CHEBI:15377"/>
    <dbReference type="ChEBI" id="CHEBI:15378"/>
    <dbReference type="ChEBI" id="CHEBI:16452"/>
    <dbReference type="ChEBI" id="CHEBI:16947"/>
    <dbReference type="ChEBI" id="CHEBI:57287"/>
    <dbReference type="ChEBI" id="CHEBI:57288"/>
    <dbReference type="EC" id="2.3.3.16"/>
  </reaction>
  <physiologicalReaction direction="left-to-right" evidence="2">
    <dbReference type="Rhea" id="RHEA:16846"/>
  </physiologicalReaction>
  <physiologicalReaction direction="right-to-left" evidence="2">
    <dbReference type="Rhea" id="RHEA:16847"/>
  </physiologicalReaction>
</comment>

Reaction description from NC-IUBMB:

Example: P17050

Previous format (based on NC-IUBMB):

<comment type="catalytic activity">
  <text evidence="6">Cleavage of non-reducing alpha-(1->3)-N-acetylgalactosamine residues from human blood group A and AB mucin glycoproteins, Forssman hapten and blood group A lacto series glycolipids.</text>
</comment>

New format (based on NC-IUBMB):

<comment type="catalytic activity">
  <reaction evidence="6">
    <text>Cleavage of non-reducing alpha-(1->3)-N-acetylgalactosamine residues from human blood group A and AB mucin glycoproteins, Forssman hapten and blood group A lacto series glycolipids.</text>
    <dbReference type="EC" id="3.2.1.49"/>
  </reaction>
</comment>

RDF format

Note: Evidence-related statements are omitted since their format does not change. In the previous format, evidence was attributed via reification of the rdfs:comment statement. In the new format, the up:catalyticActivity and up:catalyzedPhysiologicalReaction statements are reified.

Reaction description from Rhea:

Example: O36015

Previous format (based on NC-IUBMB):

uniprot:O36015
  up:annotation <O36015#SIP5A4ED6FF66BBF481> .

<O36015#SIP5A4ED6FF66BBF481>
  rdf:type up:Catalytic_Activity_Annotation ;
  rdfs:comment "S-adenosyl-L-methionine + cytidine(32)/guanosine(34) in tRNA = S-adenosyl-L-homocysteine + 2'-O-methylcytidine(32)/2'-O-methylguanosine(34) in tRNA." .

New format (based on Rhea):

uniprot:O36015
  up:annotation <O36015#SIP962CEE3C69B2533E> .

<O36015#SIP962CEE3C69B2533E>
  rdf:type up:Catalytic_Activity_Annotation ;
  up:catalyticActivity <O36015#SIP6D2D3E976AAD17F0> .

<O36015#SIP6D2D3E976AAD17F0>
  rdf:type up:Catalytic_Activity ;
  up:catalyzedReaction <http://rdf.rhea-db.org/42396> ;
  up:enzymeClass enzyme:2.1.1.205 .

Example: A0A0S3QTD0

Previous format (based on NC-IUBMB):

uniprot:A0A0S3QTD0
  up:annotation <A0A0S3QTD0#SIPF04A1EC4C8EBCB08> .

<A0A0S3QTD0#SIPF04A1EC4C8EBCB08>
  rdf:type up:Catalytic_Activity_Annotation ;
  rdfs:comment "Acetyl-CoA + H(2)O + oxaloacetate = citrate + CoA." .

New format (based on Rhea):

uniprot:A0A0S3QTD0
  up:annotation <A0A0S3QTD0#SIP8171B3125ADE4E9D> .

<A0A0S3QTD0#SIP8171B3125ADE4E9D>
  rdf:type up:Catalytic_Activity_Annotation ;
  up:catalyticActivity <A0A0S3QTD0#SIP1A91565011EC50F6> ;
  up:catalyzedPhysiologicalReaction <http://rdf.rhea-db.org/16846> ,
                                    <http://rdf.rhea-db.org/16847> .

<A0A0S3QTD0#SIP1A91565011EC50F6>
  rdf:type up:Catalytic_Activity ;
  up:catalyzedReaction <http://rdf.rhea-db.org/16845> ;
  up:enzymeClass enzyme:2.3.3.16 .

Reaction description from NC-IUBMB:

Example: P17050

Previous format (based on NC-IUBMB):

uniprot:P17050
  up:annotation <P17050#SIP0FD272930B1683DE> .

<P17050#SIP0FD272930B1683DE>
  rdf:type up:Catalytic_Activity_Annotation ;
  rdfs:comment "Cleavage of non-reducing alpha-(1->3)-N-acetylgalactosamine residues from human blood group A and AB mucin glycoproteins, Forssman hapten and blood group A lacto series glycolipids." .
  

New format (based on NC-IUBMB):

uniprot:P17050
  up:annotation <P17050#SIP0FD272930B1683DE> .

<P17050#SIP0FD272930B1683DE>
  rdf:type up:Catalytic_Activity_Annotation ;
  up:catalyticActivity <P17050#SIP0FD272930B1683DF> .

<P17050#SIP0FD272930B1683DF>
  rdf:type up:Catalytic_Activity ;
  skos:closeMatch enzyme:3.2.1.49#SIP0FD272930B1683DG ;
  up:enzymeClass enzyme:3.2.1.49 .

Change of the RDF representation of enzyme related data

We have changed the RDF representation of ENZYME records in order to refer from UniProt 'Catalytic activity' annotations to individual enzymatic activities. The range of the activity predicate has been changed to the type Catalytic_Activity.

Example: 1.11.1.21

Previous format:

enzyme:1.11.1.21
  rdf:type up:Enzyme ;
  skos:prefLabel "Catalase peroxidase" ;
  up:activity "Donor + H(2)O(2) = oxidized donor + 2 H(2)O." ;
  up:activity "2 H(2)O(2) = O(2) + 2 H(2)O." ;
  ...

New format:

enzyme:1.11.1.21
  rdf:type up:Enzyme ;
  skos:prefLabel "Catalase peroxidase" ;
  up:activity <1.11.1.21#SIP017EC216DF0EDC2A> ;
  up:activity <1.11.1.21#SIP018ED427AB1BAS3X> ;
  ...

<1.11.1.21#SIP017EC216DF0EDC2A>
  rdf:type up:Catalytic_Activity ;
  rdfs:label "Donor + H(2)O(2) = oxidized donor + 2 H(2)O." .

<1.11.1.21#SIP018ED427AB1BAS3X>
  rdf:type up:Catalytic_Activity ;
  rdfs:label "2 H(2)O(2) = O(2) + 2 H(2)O." .

Changes to the controlled vocabulary of human diseases

New diseases:

• Bone marrow failure syndrome 4
• Deafness, autosomal recessive 32, with or without immotile sperm
• Mitochondrial complex V deficiency, nuclear type 5
• Mungan syndrome
• Muscular dystrophy, limb-girdle, autosomal dominant 4
• Ovarian dysgenesis 7
• Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
• Polydactyly, postaxial, A8
• Spinocerebellar ataxia, autosomal recessive 4

Modified diseases:

• Mitochondrial complex V deficiency, nuclear 1 -> Mitochondrial complex V deficiency, nuclear type 1
• Mitochondrial complex V deficiency, nuclear 2 -> Mitochondrial complex V deficiency, nuclear type 2
• Mitochondrial complex V deficiency, nuclear 3 -> Mitochondrial complex V deficiency, nuclear type 3
• Mitochondrial complex V deficiency, nuclear 4 -> Mitochondrial complex V deficiency, nuclear type 4

Deleted diseases

• Deafness, autosomal recessive, 105

Changes to the controlled vocabulary for PTMs

New term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Murein peptidoglycan amidated serine

Changes in subcellular location controlled vocabulary

New subcellular location:

• T-tubule

Headline

You're not coming in!

Sexual reproduction is a great process to diversify the genetic pool and to accelerate evolution. However, it imposes tight constraints for success. First, sperm must meet egg, an unfertilized egg cannot develop. In addition, exactly one sperm cell has to meet one egg, polyspermy is not viable. And to ensure the survival of distinct species, the process has to be strictly species-specific. This requirement is particularly challenging in organisms in which fertilization occurs externally, as is the case for fish.

Looking for factors required for fertilization in vertebrates, Herberg et al. identified a small protein highly expressed in zebrafish (Danio rerio) oocytes. They called the protein Bouncer. Bouncer is located at the cell surface where it is attached to the membrane through a glycosylphosphatidylinositol (GPI) anchor, following cleavage of the C-terminal propeptide.

Bouncer function was investigated in knockout zebrafish. At first glance, the mutant animals did not show any overt phenotype. They were produced at the expected Mendelian rates and developed normally. When fertility was tested, there was no difference between knockout and wild-type males, but knockout females were almost completely sterile. Delivery of sperm into Bouncer-deficient eggs by intracytoplasmic sperm injection restored embryonic development, suggesting that Bouncer was involved in sperm entry during fertilization. Bouncer was indeed shown to promote sperm-egg binding. Could Bouncer play a role in species recognition during fertilization? To test this hypothesis, zebrafish Bouncer knockout eggs expressing the medaka fish (Oryzias latipes) Bouncer ortholog were generated. Medaka sperm cannot normally fertilize zebrafish eggs. Both species split apart some 200 million years ago, much earlier than we did from mice, and they share only 40% sequence identity. Amazingly the transgenic knockout eggs could be fertilized by medaka, but not zebrafish sperm. Fertility rates of individual transgenic medaka Bouncer females were found to correlate with expression levels of medaka Bouncer mRNA in eggs. In conclusion, the small 80-amino acid-long Bouncer protein plays a crucial role in species-specific fertilization. The rescue was not complete. The fertility rate was low, suggesting that other factors likely contribute to species-specific sperm-egg interaction.

Bouncer homologs exist in other vertebrate species. Its closest relative in mammals is the SPACA4 gene. Bouncer/SPACA4 germline-restricted expression was confirmed in all vertebrates tested. However, Bouncer ovary-specific expression was observed only in externally fertilizing animals, such as fish or amphibians; surprisingly, internally fertilizing vertebrates, such as reptiles and mammals, show testis-specific expression. The reason for this difference is not clear and the function of mammalian SPACA4 is not yet known.

As of this release, zebrafish and medaka Bouncer proteins have been annotated and integrated into UniProtKB/Swiss-Prot.

Changes to the controlled vocabulary of human diseases

New diseases:

• Deafness, autosomal recessive, 110
• Encephalitis/encephalopathy, mild, with reversible myelin vacuolization
• Epilepsy, familial adult myoclonic, 1
• Epilepsy, familial adult myoclonic, 6
• Epilepsy, familial adult myoclonic, 7
• Epileptic encephalopathy, early infantile, 66
• Hemolytic anemia, congenital, X-linked
• Hyperaldosteronism, familial, 2
• Immunodeficiency 57
• Immunodeficiency 58
• Inflammatory bowel disease 29
• Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities
• Intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities
• Keratolytic winter erythema
• Liddle syndrome 2
• Liddle syndrome 3
• Mental retardation, autosomal dominant 58
• Mental retardation, autosomal recessive 63
• Mental retardation, autosomal recessive 64
• Mental retardation, autosomal recessive 65
• Microcephaly, growth restriction, and increased sister chromatid exchange 2
• Neurodevelopmental disorder with cerebellar atrophy and with or without seizures
• Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum
• Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures
• Neurodevelopmental disorder with spasticity and poor growth
• Osteogenesis imperfecta 19
• Osteopetrosis, autosomal dominant 3
• Ovarian dysgenesis 6
• Peeling skin syndrome 6
• Premature ovarian failure 15
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5
• Spermatogenic failure 28
• Spermatogenic failure 29
• Spermatogenic failure 30
• Spermatogenic failure 31
• Spermatogenic failure 32
• Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

Modified disease:

• Leukodystrophy metachromatic due to saposin-B deficiency -> Metachromatic leukodystrophy due to saposin-B deficiency

Changes to keywords

New keyword:

• Translocase

Headline

Tubulin code: a long sought-after player identified

In eukaryotes, the cytoskeleton helps cells maintain their shape and internal organization, and provides mechanical support that enables cells to carry out essential functions, like division and movement. It is made of filamentous proteins, microtubules being the largest type of cytoskeletal filament. Microtubules are dynamically assembled from alpha-tubulin and beta-tubulin heterodimers, creating specific structures adapted to the cell's needs, structures that can be as different from each other as a cilium can be from a mitotic spindle. How is this variety achieved using the same highly conserved building blocks? Part of the answer lies in the so-called 'tubulin code' which involves not only the differential expression of alpha-and beta-tubulin genes (tubulin isotypes), but also a plethora of post-translational modifications (PTMs). Tubulins have a globular core and a more variable C-terminal tail that is exposed at the microtubule surface, where many PTMs occur. One of first PTMs to be reported, back in the 70s, was C-terminal reversible detyrosination, which occurs on most alpha-, but not beta-, tubulins. The enzyme catalyzing the addition of tyrosine, tubulin-tyrosine ligase or TTL, was identified not long after, but the carboxypeptidase responsible for tubulin detyrosination remained elusive until recently.

Aillaud et al. tackled the problem by developing an irreversible inhibitor of tubulin carboxypeptidase activity, followed by mass spectrometry analysis of the inhibitor targets. Nieuwenhuis et al. performed gene-trapping mutagenesis in a haploid human cell line aimed at regulators of tubulin detyrosination. Both groups identified vasohibin-1 (VASH1) and 2 (VASH2) as the major alpha-tubulin-specific carboxypeptidases. Vasohibins were formerly predicted to have a protease fold, but their enzymatic activity had not been investigated. Actually, both enzymes show low carboxypeptidase activity when assayed on their own. Full activity requires the formation of a complex with another protein, called small vasohibin-binding protein, or SVBP. This may explain why previous attempts to identify tubulin carboxypeptidase have failed. SVBP-VASH complexes act preferentially on polymerized tubulins. When microtubules disassemble, TTL adds back a tyrosine residue at the C-terminus and the tubulin detyrosination/tyrosination cycle is closed.

The physiological importance of detyrosination has to be investigated. SVBP or vasohibin knockdown in mouse hippocampal neurons results in delayed axonal differentiation. In embryos, it affects neuronal migration during brain cortex differentiation. However, mice lacking VASH1 or VASH2 do not exhibit a dramatic phenotype. It should also be noted that vasohibin depletion in cells could not completely abolish activity, suggesting the existence of yet another enzyme.

The VASH1 and VASH2 protein entries have been updated and are now available in UniProtKB/Swiss-Prot.

Changes to the controlled vocabulary of human diseases

New diseases:

• Cardiomyopathy, familial hypertrophic 27
• Charcot-Marie-Tooth disease 2DD
• Ciliary dyskinesia, primary, 38
• Coffin-Siris syndrome 7
• Congenital disorder of glycosylation 1BB
• Corneal dystrophy, posterior polymorphous, 4
• Diabetes mellitus, insulin-dependent, 5
• Ehlers-Danlos syndrome, classic type, 2
• Epileptic encephalopathy, early infantile, 65
• Epileptic encephalopathy, infantile or early childhood, 3
• Glycosylphosphatidylinositol biosynthesis defect 17
• Humerofemoral hypoplasia with radiotibial ray deficiency
• Hydrocephalus, congenital, 3, with brain anomalies
• Hyperekplexia 4
• Intellectual developmental disorder with or without epilepsy or cerebellar ataxia
• Leukodystrophy, hypomyelinating, 17
• Mastocytosis, cutaneous
• Mastocytosis, systemic
• Mental retardation, autosomal dominant 57
• Neurodevelopmental disorder with brain, liver, and lung abnormalities
• Otitis media
• Parkinsonism-dystonia, infantile, 2
• Pelger-Huet anomaly with mild skeletal anomalies
• Polycystic kidney disease 6 with or without polycystic liver disease
• Pontocerebellar hypoplasia 1D
• Proteasome-associated autoinflammatory syndrome 2
• Proteasome-associated autoinflammatory syndrome 3
• Protoporphyria, erythropoietic, 2
• Seizures, benign familial infantile, 6
• Tetraamelia syndrome 2

Modified diseases:

• Acne inversa, familial, 2 -> Acne inversa, familial, 2, with or without Dowling-Degos disease
• Anorexia nervosa 2 -> Anorexia nervosa
• Cold-induced sweating syndrome 1 -> Crisponi/Cold-induced sweating syndrome 1
• Cold-induced sweating syndrome 2 -> Crisponi/Cold-induced sweating syndrome 2
• Cold-induced sweating syndrome 3 -> Crisponi/Cold-induced sweating syndrome 3
• Ehlers-Danlos syndrome 3 -> Ehlers-danlos syndrome, hypermobility type
• Ehlers-Danlos syndrome 4 -> Ehlers-Danlos syndrome, vascular type
• Ehlers-Danlos syndrome 6 -> Ehlers-Danlos syndrome, kyphoscoliotic type, 1
• Ehlers-Danlos syndrome 7A -> Ehlers-Danlos syndrome, arthrochalasia type, 1
• Ehlers-Danlos syndrome 7C -> Ehlers-Danlos syndrome, dermatosparaxis type
• Ehlers-Danlos syndrome, autosomal recessive, cardiac valvular form -> Ehlers-Danlos syndrome, cardiac valvular type
• Ehlers-Danlos syndrome, classic type -> Ehlers-Danlos syndrome, classic type, 1
• Ehlers-Danlos syndrome due to tenascin X deficiency -> Ehlers-Danlos syndrome, classic-like
• Ehlers-Danlos syndrome, progeroid type, 2 -> Ehlers-Danlos syndrome, spondylodysplastic type, 2
• Ehlers-Danlos syndrome, with progressive kyphoscoliosis, myopathy, and hearing loss -> Ehlers-Danlos syndrome, kyphoscoliotic type, 2
• Ehlers-Danlos syndrome with short stature and limb anomalies -> Ehlers-Danlos syndrome, spondylodysplastic type, 1
• Ehlers-Danlos syndrome-like spondylocheirodysplasia -> Ehlers-Danlos syndrome, spondylodysplastic type, 3
• Encephalopathy, acute, infection-induced (herpes-specific) 8 -> Encephalopathy, acute, infection-induced, herpes-specific, 8
• Erythropoietic protoporphyria -> Protoporphyria, erythropoietic, 1
• Herpes simplex encephalitis 1 -> Encephalopathy, acute, infection-induced, Herpes-specific, 1
• Herpes simplex encephalitis 2 -> Encephalopathy, acute, infection-induced, Herpes-specific, 2
• Herpes simplex encephalitis 3 -> Encephalopathy, acute, infection-induced, Herpes-specific, 5
• Herpes simplex encephalitis 4 -> Encephalopathy, acute, infection-induced, Herpes-specific, 6
• Herpes simplex encephalitis 7 -> Encephalopathy, acute, infection-induced, Herpes-specific, 7
• Hydrocephalus, non-syndromic, autosomal recessive 1 -> Hydrocephalus, congenital, 1
• Hydrocephalus, non-syndromic, autosomal recessive 2 -> Hydrocephalus, congenital, 2, with or without brain or eye anomalies
• Hyperphosphatasia with mental retardation syndrome 5 -> Glycosylphosphatidylinositol biosynthesis defect 11
• Hypomagnesemia 5 -> Hypomagnesemia 5, renal, with or without ocular involvement
• IL21R immunodeficiency -> Immunodeficiency 56
• Isolated sulfite oxidase deficiency -> Sulfite oxidase deficiency, isolated
• May-Hegglin anomaly -> Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
• Methemoglobinemia CYB5A-related -> Methemoglobinemia and ambiguous genitalia
• Methylmalonic aciduria and homocystinuria type cblD -> Methylmalonic aciduria and homocystinuria, cblD type
• Methylmalonic aciduria and homocystinuria type cblC -> Methylmalonic aciduria and homocystinuria, cblC type
• Methylmalonic aciduria and homocystinuria type cblF -> Methylmalonic aciduria and homocystinuria, cblF type
• Nakajo syndrome -> Proteasome-associated autoinflammatory syndrome 1
• Natural killer cell and glucocorticoid deficiency with DNA repair defect -> Immunodeficiency 54
• Polycystic kidney disease 1 -> Polycystic kidney disease 1 with or without polycystic liver disease
• Polycystic kidney disease 2 -> Polycystic kidney disease 2 with or without polycystic liver disease
• Polycystic kidney disease 3 -> Polycystic kidney disease 3 with or without polycystic liver disease
• Polycystic kidney disease 4, with or without hepatic disease -> Polycystic kidney disease 4, with or without polycystic liver disease
• Polycystic liver disease 1 -> Polycystic liver disease 1 with or without kidney cysts
• Polycystic liver disease 2 -> Polycystic liver disease 2 with or without kidney cysts
• Pro-opiomelanocortinin deficiency -> Obesity, early-onset, with adrenal insufficiency and red hair
• Shwachman-Diamond syndrome -> Shwachman-Diamond syndrome 1
• Tetraamelia syndrome, autosomal recessive -> Tetraamelia syndrome 1
• Transposition of the great arteries dextro-looped 3 -> Congenital heart defects, multiple types, 6
• Tumoral calcinosis, hyperphosphatemic, familial -> Tumoral calcinosis, hyperphosphatemic, familial, 1
• Weill-Marchesani-like syndrome -> Weill-Marchesani syndrome 4

Deleted diseases

• Alport syndrome, with macrothrombocytopenia
• Bannayan-Riley-Ruvalcaba syndrome
• Cowden syndrome 2
• Cowden syndrome 3
• Epstein syndrome
• Fechtner syndrome
• Macrothrombocytopenia and progressive sensorineural deafness
• Sebastian syndrome

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• (2S)-4-hydroxyleucine
• (3S)-3-hydroxylysine
• (4S)-4,5-dihydroxyleucine
• 2-hydroxyproline
• 3',4',5'-trihydroxyphenylalanine
• 4-hydroxylysine

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

• Hydroxylated arginine -> Hydroxyarginine

UniProt website news

Deprecation of legacy REST URLs /batch and /mapping - please replace by /uploadlists

Programmatic access to our "Retrieve/IDmapping" service should be addressed to the URL path /uploadlists as shown in the code examples in the respective service help pages ID mapping and Batch retrieval.

If you have existing code for batch retrieval, you also need to specify that you are mapping to and from UniProtKB, i.e.

'from' => 'ACC+ID',
'to' => 'ACC',

(See the Perl code example in Batch retrieval.)

The obsolete URL paths /batch and /mapping have been deprecated and are no longer supported as of release 2018_09.

Headline

Human brain development: slow and steady wins the race

As mammals, we share most of our physiological processes with other animals and these similarities allow the wide use of model organisms for medical research purposes. Yet there is something special about us, abstract thought, creativity, art, culture, something linked to our big brains. The increase in size and complexity of our cerebral cortex happened recently on the evolution time scale, i.e. after the Homo lineage split apart from that of other related primates. In order to try to understand this distinctive feature of ours, several new human-specific genes involved in corticogenesis have been identified. They are produced by segmental duplications, but their functional impact on brain development remains mysterious. However, among these genes are 3 nearly identical NOTCH2 paralogs, called NOTCH2NLA, B and C for which functional clues have been recently obtained. The evolutionary history of NOTCH2NL genes is peculiar. NOTCH2 partial duplication occurred prior to the last common ancestor of human, chimpanzee, and gorilla (some 14 million years ago) leading to the creation of a truncated inactive copy, called NOTCH2NL (standing for Notch homolog 2 N-terminal-like). In the hominin lineage, some 3 to 4 million years ago, the NOTCH2 dopplegänger was repaired by gene conversion and duplicated, creating 3 new human-specific active genes NOTCH2NLA, B and C. This timeframe corresponds to the early stages of the expansion of the human neocortex.

NOTCH2NLA, B and C are expressed in radial glia neural stem cells during cortical development. These cells undergo multiple cycles of regenerative, mostly asymmetric, cell divisions, leading to the generation of diverse types of neurons while maintaining a pool of progenitors. NOTCH2NL gene expression activates the NOTCH signaling pathway, down-regulates neuronal differentiation genes, and delays the differentiation of neuronal progenitors, increasing their number, all of which ultimately results in an increase in neurons. In this context, slow development produces a huge benefit.

The chromosome 1q21.1 region hosting NOTCH2NL genes is associated with chromosome 1q21.1 deletion / duplication syndromes, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. 11 patients were analyzed : those with microcephaly had NOTCH2NLA and/or NOTCH2NLB deletions, while the macrocephaly cases were consistent with NOTCH2NLA and/or NOTCH2NLB duplications. If confirmed, these results are consistent with a crucial role for NOTCH2NL genes in human neocortex development. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, at the expense of susceptibility to recurrent neurodevelopmental disorders.

Using our big brains, we have annotated all 3 NOTCH2NL gene products in UniProtKB/Swiss-Prot and they are publicly available as of this release.

UniProtKB news

Change of the annotation topic 'Enzyme regulation' to 'Activity regulation'

In UniProtKB entries, the topic 'Enzyme regulation' was used to display information about factors that regulate the activity of enzymes, but also of transporters and microbial transcription factors. To clarify the situation, we have renamed this topic to 'Activity regulation'.

Text format

Example: P02730

Previous format:

CC   -!- ENZYME REGULATION: Phenyl isothiocyanate inhibits anion transport
CC       in vitro.

New format:

CC   -!- ACTIVITY REGULATION: Phenyl isothiocyanate inhibits anion transport
CC       in vitro.

XML format

Example: P02730

Previous format:

<comment type="enzyme regulation">
  <text>Phenyl isothiocyanate inhibits anion transport in vitro.</text>
</comment>

New format:

<comment type="activity regulation">
  <text>Phenyl isothiocyanate inhibits anion transport in vitro.</text>
</comment>

RDF format

Example: P02730

Previous format:

uniprot:P02730
  up:annotation <P02730#SIPC58AB4FDB0DD7DCA> .

<P02730#SIPC58AB4FDB0DD7DCA>
  rdf:type up:Enzyme_Regulation_Annotation ;
  rdfs:comment "Phenyl isothiocyanate inhibits anion transport in vitro." .

New format:

uniprot:P02730
  up:annotation <P02730#SIPC58AB4FDB0DD7DCA> .

<P02730#SIPC58AB4FDB0DD7DCA>
  rdf:type up:Activity_Regulation_Annotation ;
  rdfs:comment "Phenyl isothiocyanate inhibits anion transport in vitro." .

Change to the cross-references to Bgee

We have introduced an additional field in the cross-references to the Bgee database to indicate the expression pattern of the gene.

Text format

Example: P10361

DR   Bgee; ENSRNOG00000010756; Expressed in 10 organ(s), highest expression level in spleen.

XML format

Example: P10361

<dbReference type="Bgee" id="ENSRNOG00000010756">
  <property type="expression patterns" value="Expressed in 10 organ(s), highest expression level in spleen"/>
</dbReference>

This change does not affect the XSD, but may nevertheless require code changes.

RDF format

Example: P10361

uniprot:P10361
  rdfs:seeAlso <http://purl.uniprot.org/bgee/ENSRNOG00000010756> .
<http://purl.uniprot.org/bgee/ENSRNOG00000010756>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/Bgee> ;
  rdfs:comment "Expressed in 10 organ(s), highest expression level in spleen" .

Changes to the controlled vocabulary of human diseases

New diseases:

• Combined oxidative phosphorylation deficiency 36
• Congenital disorder of glycosylation with defective fucosylation
• Deafness, autosomal recessive, 26
• Deafness, autosomal recessive, 57
• Deafness, autosomal recessive, 109
• Deafness, congenital heart defects, and posterior embryotoxon
• Developmental delay, intellectual disability, obesity, and dysmorphic features
• Ehlers-Danlos syndrome, classic-like, 2
• Epileptic encephalopathy, early infantile, 63
• Epileptic encephalopathy, early infantile, 64
• Hyperostosis cranialis interna
• Jaberi-Elahi syndrome
• Leukodystrophy, hypomyelinating, 15
• Leukodystrophy, hypomyelinating, 16
• Microcephaly 21, primary, autosomal recessive
• Microcephaly 22, primary, autosomal recessive
• Microcephaly 23, primary, autosomal recessive
• Multiple mitochondrial dysfunctions syndrome 6
• Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures
• Oocyte maturation defect 5
• Osteogenesis imperfecta 18
• Premature ovarian failure 14
• Rh-null, amorph type
• Short-rib thoracic dysplasia 7/20 with polydactyly, digenic
• Spermatogenic failure 24
• Spermatogenic failure 25
• Spermatogenic failure 26
• Spermatogenic failure 27
• Spinocerebellar ataxia 47
• Spondyloepimetaphyseal dysplasia, Di Rocco type
• Tumoral calcinosis, hyperphosphatemic, familial, 2
• Tumoral calcinosis, hyperphosphatemic, familial, 3
• Ververi-Brady syndrome

Deleted diseases

• Ehlers-Danlos syndrome 7B

UniProt website news

New advanced search interface

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