SII-SWORD/CoKE huggingface dataset:
GPCR, family 2, calcitonin gene-related peptide, type 1 receptor (GPCR_2_CGRP1_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

Calcitonin gene-related peptide (CGRP) type 1 receptor (also known as Calcitonin receptor-like receptor) is a neuropeptide with diverse biological effects including potent vasodilator activity . Messenger RNA for this receptor is predominantly expressed in the lung and heart, with specific localisation to lung alveolar cells and cardiac myocytes . Mutations in the gene for this protein has been related to pontaneous miscarriage and subfertility . In the rat lung, it is associated with blood vessels; the gene may therefore play an important role in the maintenance of vascular tone . mRNA is also found in the cerebellum . The ligand for this receptor-like protein remains to be discovered.
Nudix hydrolase 6-like (Nudix_hydrolase6-like)
Type: Family

This entry represents several nudix hydrolases, including nudix hydrolase 2, 5, 6, 7, 8 and 10. Nudix hydrolases are ubiquitous proteins that hydrolyse a wide range of organic pyrophosphates, including nucleoside di- and triphosphates, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity . Nudix hydrolase 7 is an Acyl-CoA diphosphatase involved in regulating peroxisomal coenzyme A homeostasis .
Interleukin-1 alpha (IL-1_alpha)
Type: Family

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location . The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded β-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors . The β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.

The Vaccinia virus genes B15R and B18R each encode proteins with N-terminal hydrophobic sequences, possible sites for attachment of N-linked carbohydrate and a short C-terminal hydrophobic domain . These properties are consistent with the mature proteins being either virion, cell surface or secretory glycoproteins. Protein sequence comparisons reveal that the gene products are related to each other (20% identity) and to the Ig superfamily. The highest degree of similarity is to the human and murine interleukin-1 receptors, although both proteins are related to a wide range of Ig superfamily members, including the interleukin-6 receptor. A novel method for virus immune evasion has been proposed in which the product of one or both of these proteins may bind interleukin-1 and/or interleukin-6, preventing these cytokines reaching their natural receptors . A similar gene product from Cowpox virus (CPV) has also been shown to specifically bind murine IL-1 beta .

This entry represents the IL-1 family alpha (IL1A).
Interleukin-1 receptor antagonist/Interleukin-36 (IL-1RA/IL-36)
Type: Family

This entry represents IL-1RA and Interleukin-36 cytokines.

Interleukin-1 receptor antagonist (IL-1RA) binds to the IL-1 receptor, blocking the effects of Interleukin-1 alpha and interleukin-1 beta (IL-1A and IL-1B), whilst eliciting no response of its own. From sequence comparisons, it seems to have arisen by gene duplication before IL-1 diverged into IL-1A and IL-1B, as it has features of both . It seems likely to have the same fold as IL-1A and IL-1B. IL-1A and IL-1B are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis .

Interleukin-36 cytokines constitute a novel cluster of cytokines with structural and functional similarities to IL-1 . Previously designated as interleukin-1 family members 5 - 10 (IL-1F5 to IL-1F10), they have recently been reclassified according to an updated cytokine nomenclature scheme . Family members include:

interleukin-36 alpha, beta and gamma (previously IL-1F6, IL-1F8 and IL-1F9, respectively), which are pro-inflammatory and signal through IL-1Rrp2 and IL-1RAcP .

interleukin-36 receptor antagonist (previously IL-1F5), which binds IL-1Rrp2, acting as an antagonist for interleukins signalling via this route .

interleukin-37 (IL-1F7), which exerts anti-inflammatory actions by suppressing production of pro-inflammatory cytokines .

IL-1F10, whose function is unknown.
Apical membrane antigen 1 (Apmem_Ag1)
Type: Family

A novel antigen of Plasmodium falciparum has been cloned that contains a hydrophobic domain typical of an integral membrane protein. The antigen is designated apical membrane antigen 1 (AMA-1) by virtue of appearing to be located in the apical complex . AMA-1 appears to be transported to the merozoite surface close to the time of schizont rupture.

The 66kDa merozoite surface antigen (PK66) of Plasmodium knowlesi, a simian malaria, possesses vaccine-related properties believed to originate from a receptor-like role in parasite invasion of erythrocytes . The sequence of PK66 is conserved throughout plasmodium, and shows high similarity to P. falciparum AMA-1. Following schizont rupture, the distribution of PK66 changes in a coordinate manner associated with merozoite invasion. Prior to rupture, the protein is concentrated at the apical end, following which it distributes itself entirely across the surface of the free merozoite. Immunofluorescence studies suggest that, during invasion, PK66 is excluded from the erythrocyte at, and behind, the invasion interface .
Viral protein D9 (Viral_VD9)
Type: Family

The complete DNA sequence of the genome of Vaccinia virus has been determined . 198 "major" protein-coding regions and 65 overlapping "minor" regions have been identified, with a total of 263 potential genes. The genes are compactly organised along the genome, with few noncoding regions . The function of the majority of proteins encoded by these open reading frames is so far undetermined.

This entry represents a family of proteins from poxvirus, including the D9 protein from Vaccinia virus (also known as mRNA-decapping protein OPG121), a decapping Nudix enzyme that accelerates viral and cellular mRNA turnover to eliminate competing host mRNAs and allow stage-specific synthesis of viral proteins, being critical for poxvirus pathogenicity. Acceleration of the turnover of cellular transcripts may even promote the shutoff of host protein synthesis. This enzyme shows a domain organization in which a three-helix bundle is inserted into the catalytic Nudix domain .
Vaccinia virus D10, decapping enzyme (Vaccinia_D10_decapping)
Type: Family

The complete DNA sequence of the genome of Vaccinia virus has been determined . 198 "major" protein-coding regions and 65 overlapping "minor" regions have been identified, with a total of 263 potential genes. The genes are compactly organised along the genome, with few noncoding regions . The function of the majority of proteins encoded by these open reading frames is so far undetermined.

The DNA sequence of the Fowlpox virus genome corresponding to the vaccinia virus D6-A1 region has been deduced . Translation of the sequence reveals fowlpox virus gene homologues corresponding to the D6, D7, D9, D10, D11, D12, D13 and A1 genes of vaccinia virus. Insertion of a gene cartridge comprising the vaccinia virus p7.5 promoter and the lacZ gene into the fowlpox virus D8, D9 and D10 genes was carried out
in vitro
, followed by recombination into fowlpox virus . No stable insertion mutants were obtained for D10, suggesting that this gene probably encodes a function essential to virus replication .

D10 (also known as mRNA-decapping protein OPG122), like the D9 protein, contains an evolutionarily conserved MutT domain core, which is a characteristic of the NUDIX hydrolase family .
Filaggrin (Filaggrin)
Type: Family

Filaggrins are filament-associated proteins that interact with keratin intermediate filaments of terminally differentiating mammalian epidermis via disulphide bond formation . Filaggrin-2 is essential for normal cell-cell adhesion in the cornified cell layers and important for proper integrity and mechanical strength of the stratum corneum of the epidermis . They show wide species variations and their aberrant expression has been implicated in a number of keratinising disorders. The proteins are synthesised as large, insoluble, highly-phosphorylated precursors, containing multiple tandem repeats of 324 amino acids, which are not separated by a large linker. The precursor is deposited as keratohyalin granules. During terminal differentiation, it is dephosphorylated and proteolytically cleaved.
Carbohydrate-binding, CenC-like (CenC_carb-bd)
Type: Domain

The 1,4-beta-glucanase CenC from Cellulomonas fimi (

) contains two cellulose-binding domains, CBD(N1) and CBD(N2), arranged in tandem at its N terminus. These homologous CBDs are distinct in their selectivity for binding amorphous and not crystalline cellulose . Multidimensional heteronuclear nuclear magnetic resonance (NMR) spectroscopy was used to determine the tertiary structure of the N-terminal cellulose-binding domain from CenC (represented by this entry) . Its tertiary structure is strikingly similar to that of the bacterial 1,3-1,4-beta-glucanases, as well as other sugar-binding proteins with jelly-roll folds.

Endo-1,4-beta-xylanase C from Paenibacillus barcinonensis (XynC) and Cellulose 1,4-beta-cellobiosidase from Acetivibrio thermocellus (CelK) are also part of this group.
WIF domain (WIF)
Type: Domain

Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1WD) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands.

This entry represents the WIF domain, it is found in the RYK tyrosine kinase receptors and WIF the Wnt-inhibitory-factor. The domain is extracellular and contains two conserved cysteines that may form a disulphide bridge. This domain is Wnt binding in WIF, and it has been suggested that RYK may also bind to Wnt . The WIF domain of WIF-1 was suggested to have a function in inhibiting Wnt signalling .
W2 domain (W2_domain)
Type: Domain

Translation initiation is a sophisticated, well regulated and highly coordinated cellular process in eukaryotes, in which at least 11 eukaryotic initiation factors (eIFs) are included. The W2 domain (two invariant tryptophans) is a region of ~165 amino acids which is found in the C terminus of the following eIFs :

Eukaryotic translation initiation factor 2B epsilon (eIF-2B-epsilon).

Eukaryotic translation initiation factor 4 gamma (eIF-4-gamma).

Eukaryotic translation initiation factor 5 (eIF-5), a GTPase-activating protein (GAP) specific for eIF2.

The W2 domain has a globular fold and is exclusively composed out of α-helices . The structure can be divided into a structural C-terminal core onto which the two N-terminal helices are attached. The core contains two aromatic/acidic residue-rich regions (AA boxes), which are important for mediating protein-protein interactions.
Integrase, N-terminal zinc-binding domain (Integrase_Zn-bd_dom_N)
Type: Domain

Retroviral integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains: an N-terminal zinc binding domain, a central catalytic core and a C-terminal DNA-binding domain . Often found as part of the POL polyprotein.
SCAN domain (SCAN_dom)
Type: Domain

A number of C2H2-zinc finger proteins contain a highly conserved N-terminal motif termed the SCAN (named after SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) domain. The SCAN domain has been shown to be able to mediate homo- and hetero-oligomerisation . These proteins can either activate or repress transcription, although isolated recombinant SCAN domains do not modulate significantly the transcription . In addition to these zinc finger transcription factors, an isolated SCAN domain without adjacent zinc finger motifs has been identified in some proteins . It has been noted that the SCAN domain resembles a domain-swapped version of the C-terminal domain of the HIV capsid protein .

The SCAN domain is enriched in hydrophobic and negatively charged residues with a L-X(6)-L motif at its core. This core is flanked by A, E, L, M, H and C residues that are frequently found in α-helices . Predictions of the secondary structure of the domain suggest the presence of at least three α-helices that are separated from one another by short looped regions bounded by proline residues . It has been shown to be a selective oligomerization domain that mediates homotypic and heterotypic interactions between SCAN box containing proteins .
G/T mismatch-specific thymine DNA glycosylasee TDG-like, eukaryotes (TDG-like_euk)
Type: Family

This entry includes a group of eukaryotic G/U mismatch-specific DNA glycosylases, including the uracil DNA glycosylase from fission yeasts and the thymine DNA glycosylase from animals. They excise the mismatched base from G:X mismatches, where X is uracil, thymine or 5-hydroxymethyluracil (5hmU). The mammalian thymine DNA glycosylase (TDG) may be involved in active DNA demethylation via the base excision repair pathway . It can also act as a transcriptional co-activator or co-repressor .

G:U mismatches resulting from deamination of cytosine are the most common pro-mutagenic lesions occurring in DNA. Uracil is removed in a base-excision repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both single- and double-stranded DNA. The uracil DNA glycosylase family 2 consists of thymine DNA glycosylase (TDG) from eukaryotes and mismatch-specific uracil DNA glycosylase (MUG) from prokaryotes.

Thymine DNA glycosylases (TDG) in eukaryotic organisms are known for their double-stranded glycosylase activity on guanine/uracil (G/U) base pairs . In human TDG removes uracil and thymine from G:U and G:T mismatches in double-stranded DNA . In E. coli MUG is highly specific to G:U mismatches but also repairs G:T mismatches at high enzyme concentration. Structural studies of E. coli MUG reveal its structural homology to UDG despite low sequence identity. It has a specific uracil-binding pocket located in a DNA-binding groove and this specificity is likely the result of a multistep lesion recognition process .
AUX/IAA protein (AUX_IAA)
Type: Family

The Aux/IAA proteins are key regulators of auxin-modulated gene expression . The plant hormone auxin (indole-3-acetic acid, IAA) regulates diverse cellular and developmental responses in plants, including cell division, expansion, differentiation and patterning of embryo responses . Auxin can regulate the gene expression of several families, including GH3 and SAUR, as well as Aux/IAA itself. The Aux/IAA proteins act as repressors of auxin-induced gene expression, possibly through modulating the activity of DNA-binding auxin response factors (ARFs). Aux/IAA and ARF are thought to interact through C-terminal protein-protein interaction domains found in both Aux/IAA and ARF.

Recent evidence suggests that Aux/IAA proteins can also mediate light responses . Some members of the Aux/IAA family are longer and contain an N-terminal DNA binding domain and may have an early function in the establishment of vascular and body patterns in embryonic and post-embryonic development in some plants.
AraC-type arabinose-binding/dimerisation domain (AraC-bd)
Type: Domain

This entry defines the ligand-binding and dimerisation domain of the bacterial regulatory protein AraC and other HTH-type transcriptional regulators. The crystal structure of the arabinose-binding and dimerisation domain of the Escherichia coli gene regulatory protein AraC was determined in the presence and absence of L-arabinose. The arabinose-bound molecule shows that the protein adopts an unusual fold, binding sugar within a β-barrel and completely burying the arabinose with the N-terminal arm of the protein. Dimer contacts in the presence of arabinose are mediated by an antiparallel coiled-coil. In the uncomplexed protein, the N-terminal arm is disordered, uncovering the sugar-binding pocket and allowing it to serve as an oligomerisation interface .
Mu-type HTH domain (Mu-type_HTH)
Type: Domain

Transposons are mobile genetic elements that move from one DNA site to another within their host's genome, often with profound biological consequences. The Mu genome is the largest and most efficient transposon known. The Mu transposase (MuA) is a multidomain protein, which is responsible for translocation of the Mu genome. Mu transposase can be divided into three structurally distinct domains, each with specific functions. The amino- terminal domain (30kDa) is responsible for sequence-specific DNA binding and can further be subdivided into two separate subdomains, which bind an internal activation sequence (IAS) and the ends of the phage genome, respectively. A highly homologous IAS binding domain is also present in the Mu repressor protein (MuR), but its binding promotes lysogeny of the phage by repressing the expression of genes required for lytic growth and by directly blocking MuA access to the IAS. The IAS binding domains of the MuR and MuA proteins are DNA-binding, winged helix-turn-helix (wHTH) domains of about 75 residues (Mu- type HTH) .

The Mu-type HTH domain consists of a three-membered α-helical bundle buttressed by a three-stranded antiparallel β-sheet with an overall B1-H1- T-H2-B2-W-B3-H3 topology (where B,H,T and W stand for β-strand, alpha- helix, turn and wing, repectively. Helices H1 and H2 and the seven-residue turn connecting them comprise a helix-turn-helix (HTH) motif. While the general appearance of the Mu-type DNA-binding domain is similar to that of other winged HTH proteins, the connectivity of the secondary structure elements is permuted. Hence this fold represents a novel class of winged HTH DNA-binding domain .
E2F/DP family, winged-helix DNA-binding domain (E2F_WHTH_DNA-bd_dom)
Type: Domain

This entry represents the DNA-binding domain of the E2F and DP proteins, which have a fold related to the winged-helix DNA-binding motif . The mammalian transcription factor E2F plays an important role in regulating the expression of genes that are required for passage through the cell cycle. Multiple E2F family members have been identified that bind to DNA as heterodimers, interacting with proteins known as DP - the dimerisation partners .
Glycoside hydrolase, family 70, catalytic domain (Glyco_hydro70cat)
Type: Domain

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glucosyltransferases or sucrose 6-glycosyl transferases (GTF-S) (

,

) catalyse the transfer of D-glucopyramnosyl units from sucrose onto acceptor molecules . This entry represents a domain that roughly corresponds to the N-terminal catalytic domain of the enzyme. Members of this family also contain the putative cell wall binding domain

which corresponds with the C-terminal glucan-binding domain.
ATP synthase YMF19-like, N-terminal (YMF19-like_N)
Type: Domain

This entry represents a domain found at the N terminus of subunit 8 (or YMF19) of the F0 complex of mitochondrial F-ATPases from plants and algae . This subunit is sometimes found in association and N-terminal to

, in higher plants. Subunit 8 differs in sequence between plants, Metazoa (

) and fungi (

) .
Cytochrome c552 (Cyt_c552)
Type: Family

The enzyme cytochrome c nitrite reductase (c552) catalyses the six-electron reduction of nitrite to ammonia as one of the key steps in the biological nitrogen cycle, where it participates in the anaerobic energy metabolism of dissimilatory nitrate ammonification. Cytochrome c nitrite reductase from Sulfurospirillum deleyianum is a functional dimer, with 10 close-packed haem groups of type c and an unusual lysine-coordinated high-spin haem at the active site .