SII-SWORD/CoKE huggingface dataset:
Alpha-synuclein (Synuclein_alpha)
Type: Family

Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumours . The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved α-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins .

Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals . The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression . Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses .

This entry represents alpha-synuclein, which regulates synaptic vesicle trafficking and subsequent neurotransmitter release . It also acts as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of SNAREs . Synelfin from the zebra finch is a homologue of the human alpha-synuclein and may serve a novel function critical to the regulation of vertebrate neural plasticity . It is regulated during the critical period for song learning.
Beta-synuclein (Synuclein_beta)
Type: Family

Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors . The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved α-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins .

Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals . The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression . Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses .

Beta-synuclein, also known as PNP 14, is expressed in the brain, specifically in synapses around neurons, but not in glial cells. The protein, which has been designated a phosphoneuroprotein, has been found to be phosphorylated in vitro and in vivo . It is believed that the physiological functions of beta-synuclein may be controlled by the phosphorylation reaction.
Gamma-synuclein (Synuclein_gamma)
Type: Family

Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors . The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved α-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins .

Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals . The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression . Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses .
Ornatin (Ornatin)
Type: Family

Ornatin is a potent glycoprotein IIb-IIIa (GP IIb-IIIa) antagonist and platelet aggregation inhibitor . The protein is 41-52 residues in length and contains the RGD recognition motif common in adhesion proteins, and 6 conserved cysteine residues. The sequences of ornatin isoforms B, C, D and E are highly similar, while isoforms A2 and A3 are less similar, lacking the N-terminal 9 residues. Ornatins share ~40% identity with decorsin, a GP IIb-IIIa antagonist isolated from the leech (Macrobdella decora) .
DNA/RNA helicase, ATP-dependent, DEAH-box type, conserved site (DNA/RNA_helicase_DEAH_CS)
Type: Conserved_site

A number of eukaryotic and prokaryotic proteins have been characterised on the basis of their structural similarity. They all seem to be involved in ATP-dependent, nucleic-acid unwinding. There are two subfamilies of such proteins, the D-E-A-D-box and D-E-A-H-box families. Proteins that belong to the subfamily which have His instead of the second Asp are said to be 'D-E-A-H-box' proteins .

Proteins currently known to belong to this subfamily include yeast PRP2, PRP16, PRP22 and PRP43, involved in various ATP-requiring steps of the pre-mRNA splicing process; fission yeast prh1, which my be involved in pre-mRNA splicing; Drosophila male-less (mle) protein required in males for dosage compensation of X chromosome linked genes; yeast RAD3, a DNA helicase involved in excision repair of DNA damaged by UV light, bulky adducts or cross-linking agents; fission yeast rad15 (rhp3) and mammalian DNA excision repair protein XPD (ERCC-2); yeast CHL1 (or CTF1), which is important for chromosome transmission and normal cell cycle progression in G(2)/M; yeast TPS1, Caenorhabditis elegans hypothetical proteins C06E1.10 and K03H1.2; Poxviruses' early transcription factor 70kDa subunit which acts with RNA polymerase to initiate transcription from early gene promoters; Vaccinia virus putative helicase I8; and Escherichia coli putative RNA helicase hrpA. All these proteins share a number of conserved sequence motifs. Some of them are specific to this family while others are shared by other ATP-binding proteins or by proteins belonging to the helicases 'superfamily' .
Adenosine deaminase/editase (A_deamin)
Type: Domain

Editase (

) are enzymes that alter mRNA by catalyzing the
site-selective deamination of adenosine residue into inosine residue.
The editase domain contains the active site and binds three Zn atoms .

Several editases share a common global arrangement of domains, from N to C terminus: two
'double-stranded RNA-specific adenosine deaminase' (DRADA) repeat domains, followed by
three 'double-stranded RNA binding' (DsRBD) domains, followed by
the editase domain. Other editases have a simplified domains structure with no
DRADA_REP and possibly fewer DSRBD domains. Editase that deaminate cytidine are not detected by this signature.
Peptidase M24A, methionine aminopeptidase, subfamily 1 (Pept_M24A_MAP1)
Type: Family

This group of metallopeptidases belong to MEROPS peptidase family M24 (clan MG), subfamily M24A.

Methionine aminopeptidase (

) (MAP) catalyses the hydrolytic cleavage of the N-terminal methionine from newly synthesised polypeptides if the penultimate amino acid is small, with different tolerance to Val and Thr at this position . All MAP studied to date are monomeric proteins that require cobalt ions for activity. Two subfamilies of MAP enzymes are known to exist . While being evolutionary related, they only share a limited amount of sequence similarity, mostly clustered around the residues shown to be involved in cobalt-binding in Escherichia coli MAP . Subfamily 1 consists of enzymes from prokaryotes as well as eukaryotic MAP-1, while the second group (

) is made up of archaeal MAP and eukaryotic MAP-2.
Peptidase M24A, methionine aminopeptidase, subfamily 2 (Pept_M24A_MAP2)
Type: Family

This group of metallopeptidases belong to MEROPS peptidase family M24 (clan MG), subfamily M24A.

Methionine aminopeptidase (

) (MAP) catalyses the hydrolytic cleavage of the N-terminal methionine from newly synthesised polypeptides if the penultimate amino acid is small, with different tolerance to Val and Thr at this position . All MAP studied to date are monomeric proteins that require cobalt ions for activity. Two subfamilies of MAP enzymes are known to exist . While being evolutionary related, they only share a limited amount of sequence similarity mostly clustered around the residues shown, in the Escherichia coli MAP , to be involved in cobalt-binding. The first family consists of enzymes from prokaryotes as well as eukaryotic MAP-1 (

), while the second group is made up of archaeal MAP and eukaryotic MAP-2 and includes proteins which do not seem to be MAP, but that are clearly evolutionary related such as mouse proliferation-associated protein 1 and fission yeast curved DNA-binding protein.
Dipeptidylpeptidase IV, N-terminal domain (Peptidase_S9B_N)
Type: Domain

This domain defines serine peptidases belonging to MEROPS peptidase family S9 (clan SC), subfamily S9B (dipeptidyl-peptidase IV). The protein fold of the peptidase domain for members of this family resembles that of serine carboxypeptidase D, the type example of clan SC. This domain is an alignment of the region to the N-terminal side of the active site, which is found in

.

Dipeptidyl-peptidase IV (

) is also called adenosine deaminase-binding protein (ADA-binding protein) or CD26. The exopeptidase cleaves off N-terminal X-Pro or X-Ala dipeptides from polypeptides (dipeptidyl peptidase IV activity). It serves as the costimulatory molecule in T cell activation and is an associated marker of autoimmune diseases, adenosine deaminase-deficiency and HIV pathogenesis .
Peptidase S9A, prolyl oligopeptidase (Peptidase_S9A)
Type: Family

This group of serine peptidases belong to MEROPS peptidase family S9 (clan SC), subfamily S9A (prolyl oligopeptidase) which includes PREP and PREPL from human , fungal prolyl oligopeptidases such as ophP, ledP, dbiP which are part of the gene cluster that mediates the biosynthesis of omphalotin A, lentinulin A, and dendrothelin A, respectively, methylated cyclic dodecapeptides with nematodicidal activity .

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .
Palmitoyl protein thioesterase (Palm_thioest)
Type: Family

This entry represents the palmitoyl protein thioesterase family. Its members include palmitoyl-protein thioesterase 1 and lysosomal thioesterase 2 (PPT1 and PPT2). PPT1 is responsible for the removal of a palmitate group from its substrate proteins, which may include presynaptic proteins like SNAP-25, cysteine string protein (CSP), dynamin, and synaptotagmin . PPT2 removes thioester-linked fatty acyl groups from various substrates including S-palmitoyl-CoA . PPT1 and -2 perform non-redundant roles in lysosomal thioester catabolism .

Mutations in the PPT1 gene cause infantile-onset neuronal ceroid lipofuscinosis (INCL), which is a severe pediatric neurodegenerative disorder .

This entry also includes uncharacterised proteins from fungi and plants.
Carbamoyl-phosphate synthase small subunit, N-terminal domain (CarbamoylP_synth_ssu_N)
Type: Domain

This entry represents the N-terminal domain of the small subunit of carbamoyl phosphate synthase. Structurally, it forms a 3-layer β/β/α fold of a type that is thought to be mobile in most proteins that carry it .
Bcl2-like (Bcl2-like)
Type: Family

B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes . Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways .

Bcl-2 and its relatives are functionally classified as either antiapoptotic or proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins .

The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif . Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins .

This entry represents the Bcl2 family and related proteins, including E1B 19K protein (also known as E1B protein, small T-antigen), which is a putative adenovirus Bcl-2 homologue that inhibits E1A induced apoptosis and hence prolongs the viability of the host cell.
Peptidoglycan binding-like (Peptidoglycan-bd-like)
Type: Domain

This entry represents peptidoglycan binding domain (PGBD), as well as related domains that share the same structure. PGBD may have a general peptidoglycan binding function. It has a core structure consisting of a closed, three-helical bundle with a left-handed twist. It is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation . Examples are:

Muramoyl-pentapeptide carboxypeptidase (

)

N-acetylmuramoyl-L-alanine amidase cwlA precursor (cell wall hydrolase, autolysin,

)

Autolytic lysozyme (1,4-beta-N-acetylmuramidase, autolysin,

)

Membrane-bound lytic murein transglycosylase B

Zinc-containing D-alanyl-D-alanine-cleaving carboxypeptidase, VanX .

Many of the proteins having this domain are as yet uncharacterised. However, some are known to belong to MEROPS peptidase family M15 (clan MD), subfamily M15A metallopeptidases. A number of the proteins belonging to subfamily M15A are non-peptidase homologues as they either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity.

Eukaryotic enzymes can contain structurally similar PGBD-like domains. Matrix metalloproteinases (MMP), which catalyse extracellular matrix degradation, have N-terminal domains that resemble PGBD. Examples are gelatinase A (MMP-2), which degrades type IV collagen , stromelysin-1 (MMP-3), which plays a role in arthritis and tumour invasion , and gelatinase B (MMP-9) secreted by neutrophils as part of the innate immune defence mechanism . Several MMPs are implicated in cancer progression, since degradation of the extracellular matrix is an essential step in the cascade of metastasis .
PUA domain (PUA)
Type: Domain

The PUA (PseudoUridine synthase and Archaeosine transglycosylase) domain was named after the proteins in which it was first found . PUA is a highly conserved RNA-binding motif found in a wide range of archaeal, bacterial and eukaryotic proteins, including enzymes that catalyse tRNA and rRNA post-transcriptional modifications, proteins involved in ribosome biogenesis and translation, as well as in enzymes involved in proline biosynthesis . The structures of several PUA-RNA complexes reveal a common RNA recognition surface, but also some versatility in the way in which the motif binds to RNA . This domain has an α/β architecture consisting of six β-strands and two short α-helices . PUA motifs are involved in dyskeratosis congenita and cancer, pointing to links between RNA metabolism and human diseases .
DAHP synthetase, class II (DAHP_synth_2)
Type: Family

Members of the 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthetase family (

) catalyse the first step in aromatic amino acid biosynthesis from chorismate. Class I (see

) includes bacterial and yeast enzymes; class II includes higher plants and various microorganisms . They have minimal sequence identity and different regulatory and oligomeric properties, however, they have structural similarities that indicate a common ancestry for the class I and class II DAHPSs .

The first step in the common pathway leading to the biosynthesis of aromatic compounds is the stereospecific condensation of phosphoenolpyruvate (PEP) and D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) . This reaction is catalyzed by DAHP synthase, a metal-activated enzyme, which in microorganisms is the target for negative-feedback regulation by pathway intermediates or by end products.
Ferric-uptake regulator (FUR)
Type: Family

The Ferric uptake regulator (Fur) family includes metal ion uptake regulator proteins, which are responsible for controlling the intracellular concentration of iron in many bacteria. The Fur protein (a dimer having one Fe
2+
coordinated per monomer) acts as an iron-responsive,
DNA-binding repressor protein that binds to a 'Furbox' with the consensus sequence GATAATGATAATCATTATC in the promoter of iron-regulated genes. Under low-iron condition, the Fur protein is released from the promoter and transcription resumed . Some members sense metal ions other than Fe
2+
. For example, the zinc uptake regulator (Zur) responds to Zn
2+
, the manganese uptake regulator (Mur) responds to Mn
2+
, and the nickel uptake regulator (Nur) responds to Ni
2+
. Other members sense signals other than metal ions. For example, PerR, a metal-dependent sensor of hydrogen peroxide. PerR regulates DNA-binding activity through metal-based protein oxidation, and co-ordinates Mn
2+
or Fe
2+
at its regulatory site . Furs can also control zinc homeostasis and is the subject of research on the pathogenesis of mycobacteria . Fur family proteins contain an N-terminal winged-helix DNA-binding domain followed by a dimerization domain; this entry spans both those domains .
PWI domain (PWI_dom)
Type: Domain

The PWI domain, named after a highly conserved PWI tri-peptide located within its N-terminal region, is a ~80 amino acid module, which is found either at the N terminus or at the C terminus of eukaryotic proteins involved in pre-mRNA processing . It is generally found in association with other domains such as RRM and RS. The PWI domain is a RNA/DNA-binding domain that has an equal preference for single- and double-stranded nucleic acids and is likely to have multiple important functions in pre-mRNA processing . Proteins containing this domain include the SR-related nuclear matrix protein of 160kDa (SRm160) splicing and 3'-end cleavage-stimulatory factor, and the mammalian splicing factor PRP3. This domain is also present in Rmn1 from S.pombe, a component of a MTREC submodule, which promotes degradation of meiotic mRNAs and regulatory ncRNAs, and is the major nuclear exosome targeting complex for cryptic unstable transcripts (CUTs) and unspliced pre-mRNAs . Rmn1 homologues from human RBM26/27 may be involved in turnover of nuclear polyadenylated RNA and are important for PAXT-mediated nuclear RNA decay .

The PWI domain is a soluble, globular and independently folded domain which consists of a four-helix bundle, with structured N- and C-terminal elements .
Arterivirus nucleocapsid (Arte_nucleocap)
Type: Family

Arterivirus are ssRNA positive-strand viruses with no DNA stage in their replication cycle. This family contains the viral nucleocapsid protein, which encapsidates the viral ssRNA.

Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of both severe and persistent respiratory disease and reproductive failure in pigs worldwide. The PRRSV virion contains a core made of the 123 amino acid nucleocapsid (N or VP1) protein, a product of the ORF7 gene. The crystal structure of the capsid-forming domain of the nucleocapsid protein has been determined to 2.6 A resolution. The protein exists as a tight dimer forming a four-stranded β sheet floor superposed by two long α helices and flanked by two N- and two C-terminal α helices. The structure represents a new class of viral capsid-forming domains, distinctly different from those of other known enveloped viruses, but reminiscent of the coat protein of bacteriophage MS2 .
Nematode cuticle collagen, N-terminal (Col_cuticle_N)
Type: Domain

The function of this domain is unknown. It is found in the N-terminal region of nematode cuticle collagens (see

). Cuticle is a tough elastic structure secreted by hypodermal cells and is primarily composed of collagen proteins .
Transcription factor, K-box (TF_Kbox)
Type: Domain

MADS genes in plants encode key developmental regulators of vegetative and reproductive development. The majority of the plant MADS proteins share a stereotypical MIKC structure. It comprises (from N- to C-terminal) an N-terminal domain, which is, however, present only in a minority of proteins; a MADS domain (see

,

), which is the major determinant of DNA-binding but which also performs dimerisation and accessory factor binding functions; a weakly conserved intervening (I) domain, which constitutes a key molecular determinant for the selective formation of DNA-binding dimers; a keratin-like (K-box) domain, which promotes protein dimerisation; and a C-terminal (C) domain, which is involved in transcriptional activation or in the formation of ternary or quaternary protein complexes. The 80-amino acid K-box domain was originally identified as a region with low but significant similarity to a region of keratin, which is part of the coiled-coil sequence constituting the central rod-shaped domain of keratin .

The K-box protein-protein interaction domain which mediates heterodimerization of MIKC-type MADS proteins contains several heptad repeats in which the first and the fourth positions are occupied by hydrophobic amino acids suggesting that the K-box domain forms three amphipathic α-helices referred to as K1, K2, and K3 .