SII-SWORD/CoKE huggingface dataset:
Angiotensin II receptor type 2 (ATII_AT2_rcpt)
Type: Family

Angiotensin II is a blood-borne hormone produced in the circulation, it is also formed in many tissues such as the brain, kidney, heart, and blood vessels, where angiotensin II functions as a paracrine and autocrine hormone. The known actions of angiotensin II are mediated through two angiotensin receptor subtypes, Angiotensin II receptor 1 and angiotensin II receptor 2, which are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family. These subtypes are important in the renin-angiotensin system, as they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II . They also stimulate increased fluid intake and regulate the neuroendocrine system .

This entry represents angiotensin II receptor type 2 (AT2), which plays an important role in the CNS and cardiovascular functions mediated by the renin-angiotensin system. The AT2 receptor is highly expressed in various foetal tissues, with lower levels in the brain and reproductive tissues . It appears to be up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing . Depending on the tissue type, activation of the AT2 receptor also appears to stimulate intracellular mechanisms involving Tyr and Ser/Thr phosphatases, which leads to the inactivation of the AT1 and growth factor activated kinases . However, when inducing cell differentiation, the AT2 receptor can also stimulate MAP kinases Erk1/Erk2 . As a consequence, there is an inactivation of MAP kinase, promotion of apoptosis, repolarization trough opening of delayed-rectifier K+ channels and calcium and voltage activated potassium channel, closing of T -type Ca2+ channels and vasodilation . Through its phosphatase activity, the AT2 receptor regulates the NF-kappaB pathway and interferes with the inflammatory process . The AT2 receptor does not require receptor phosphorylation or heterotrimeric G alpha/beta/gamma protein to be active .
Papillomavirus E7 (Papilloma_E7)
Type: Family

This family includes the E7 oncoprotein from various papillomaviruses . Along with E5 and E6 their activities seem to be especially important for viral oncogenesis. E5 is located at the cell surface and reduces cell gap-gap junction communication. In cervical cancer E5 is expressed in earlier stages of neoplastic transformation of the cervical epithelium during viral infection. The role of E7 is less well understood but it has been shown to impede growth arrest signals in both NIH 3T3 cells and HFKs and that this correlates with elevated cdc25A gene expression. This deregulation of cdc25A is linked to disruption of cell cycle arrest .
Haemagglutinin, influenzavirus A (Hemagglutn_influenz_A)
Type: Family

Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics . The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.

The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets . Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two α helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.

This entry represents haemagglutinin from influenza virus A. The influenza A HAs can be divided into group 1 encompassing H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18, and group 2 including H3, H4, H7, H10, H14, and H15 subtypes . This entry also includes HA from Bat-derived influenza-like viruses H17N10 (

) .
Cof family (Cof)
Type: Family

The Haloacid Dehydrogenase (HAD) superfamily includes phosphatases, phosphonatases, P-type ATPases, beta-phosphoglucomutases, phosphomannomutases, and dehalogenases, which are involved in a variety of cellular processes ranging from amino acid biosynthesis to detoxification . Proteins in this entry are mostly uncharacterised, though they form a distinct subgroup within the HAD superfamily. Members are found almost exclusively in bacteria and many species contain several paralogs, for example Escherichia coli contains a total of six proteins from this entry. Sequence similarities suggest that these enzymes are phosphatases which work on phosphorylated sugars.

This entry represents a family belonging to the HAD superfamily. It is named after E. coli Cof and is notable for the large number of paralogues in many species. Cof is a phosphatase that catalyzes the hydrolysis of HMP-PP (4-amino-2-methyl-5-hydroxymethylpyrimidine pyrophosphate) to HMP-P (4-amino-2-methyl-5-hydroxymethylpyrimidine phosphate) .

E. coli YbiV (

) also belongs to this group and has been experimentally characterised . This enzyme catalyzes the hydrolysis of sugar phosphate to sugar and inorganic phosphate. It has a wide substrate specificity, catalyzing the hydrolysis of ribose-5-phosphate and glucose-6-phosphate most efficiently, but it is not known if these are the real substrates in vivo. The protein appears to be a monomer that contains two domains, an α-β hydrolase domain that forms a Rossman fold, and an α-β domain. The active site is found in a negatively charged cavity found at the interface between the two domains.
Ciliary neurotrophic factor, CNTF (Ciliary_neurotrophic_fac_CNTF)
Type: Family

Ciliary neurotrophic factor (CNTF) is a member of the gp130 family of cytokines. CNTF is a survival factor for various neuronal cell types and seems to prevent the degeneration of motor axons after axotomy suggesting it may be a potential therapeutic for treating neurodegeneration and nerve injury. CNTF acts on oligodendrocytes by favoring their final maturation, and this effect is mediated through the 130kDa glycoprotein receptor common to the CNTF family and transduced through the Janus kinase pathway. The functional receptor complex of CNTF is composed of the CNTF receptor alpha (CNTFR), gp130 and the leukemia inhibitory factor receptor (LIFR).
EGF-type aspartate/asparagine hydroxylation site (EGF-type_Asp/Asn_hydroxyl_site)
Type: PTM

Post-translational hydroxylation of aspartic acid or asparagine to form erythro-beta-hydroxyaspartic acid or erythro-beta-hydroxyasparagine has been identified in a number of proteins with domains homologous to epidermal growth factor (EGF). Examples of such proteins are the blood coagulation protein factors VII, IX and X, proteins C, S, and Z, the LDL receptor, thrombomodulin, etc. Based on sequence comparisons of the EGF-homology region that contains hydroxylated Asp or Asn, a consensus sequence has been identified that seems to be required by the hydroxylase(s).
Reovirus, outer capsid sigma 3 (Reo_capsid_sigma3)
Type: Family

Reoviruses are double-stranded RNA viruses that lack a membrane envelope. Their capsid is organised in two concentric icosahedral layers: an inner core and an outer capsid layer. The outer capsid is made up of the major proteins mu1 and sigma3, and the minor protein sigma1. The inner core structure is composed of the major core proteins lambda1 and sigma2, core spike protein lambda2, and minor core proteins lambda3 and mu2. The inner core encases the 10 segments of double-stranded RNA (dsRNA) which comprise the genome .
Ran binding domain (Ran_bind_dom)
Type: Domain

Ran is an evolutionary conserved member of the Ras superfamily that regulates all receptor-mediated transport between the nucleus and the cytoplasm. Ran Binding Protein 1 (RanBP1) has guanine nucleotide dissociation inhibitory activity, specific for the GTP form of Ran and also functions to stimulate Ran GTPase activating protein(GAP)-mediated GTP hydrolysis by Ran. RanBP1 contributes to maintaining the gradient of RanGTP across the nuclear envelope high (GDI activity) or the cytoplasmic levels of RanGTP low (GAP cofactor) .

All RanBP1 proteins contain an approx 150 amino acid residue Ran binding domain. Ran BP1 binds directly to RanGTP with high affinity.

There are four sites of contact between Ran and the Ran binding domain. One of these involves binding of the C-terminal segment of Ran to a groove on the Ran binding domain that is analogous to the surface utilised in the EVH1-peptide interaction . Nup358 contains four Ran binding domains. The structure of the first of these is known .
Toll/interleukin-1 receptor homology (TIR) domain (TIR_dom)
Type: Domain

This entry represents the Toll/interleukin-1 receptor (TIR) domain, which is the conserved cytoplasmic domain of approximately 200 amino acids, found in Toll-like receptors (TLRs) and their adaptors. Proteins containing this domain can also be found in plants, where they mediate disease resistance , and in bacteria, where they have been associated with virulence. Interestingly, the TIR domains from proteins present in all three major domains of life have been shown to cleave nicotinamide adenine dinucleotide (NAD+). In plants, TIR domains require self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase for cell death induction and NAD+ cleavage activity . It has been suggested that the primordial function of the TIR domain is the enzymatic cleavage of NAD+ and that the scaffolding function, which is best characterised in mammalian TIR domains involved in innate immunity, may be a more recent evolutionary adaptation .

Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) superfamily are both involved in innate antibacterial and antifungal immunity in insects as well as in mammals. These receptors share a conserved cytoplasmic domain of approximately 200 amino acids, known as the Toll/IL-1R homologous region (TIR). The similarity between TLRs and IL-1Rs is not restricted to sequence homology since these proteins also share a similar signalling pathway. They both induce the activation of a Rel type transcription factor via an adaptor protein and a protein kinase . Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain . Besides the mammalian and Drosophila proteins, a TIR domain is also found in a number of plant cytoplasmic proteins implicated in host defense .

Site directed mutagenesis and deletion analysis have shown that the TIR domain is essential for Toll and IL-1R activities. Sequence analysis have revealed the presence of three highly conserved regions among the different members of the family: box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W surrounded by basic residues). It has been proposed that boxes 1 and 2 are involved in the binding of proteins involved in signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal element .

Resolution of the crystal structures of the TIR domains of human Toll-like receptors 1 and 2 has shown that they contain a central five-stranded parallel β-sheet that is surrounded by a total of five helices on both sides, with connecting loop structures . The loop regions appear to play an important role in mediating the specificity of protein-protein interactions .
Cell division protein FtsZ (Cell_div_FtsZ)
Type: Family

In bacteria, FtsZ is an essential cell division protein involved in the initiation of this event. It assembles into a cytokinetic ring on the inner surface of the cytoplasmic membrane at the place where division will occur. The ring serves as a scaffold that is disassembled when septation is completed. FtsZ ring formation is initiated at a single site on one side of the bacterium and appears to grow bidirectionally. In Escherichia coli, MinCD

, encoded by the MinB locus, form a complex which appears to block the formation of FtsZ rings at the cell poles, at the ancient mid cell division sites, whilst MinE, encoded at the same locus, specifically prevents the action of MinCD at mid cell.

FtsZ is a GTP binding protein with a GTPase activity. It undergoes GTP-dependent polymerisation into filaments (or tubules) that seem to form a cytoskeleton involved in septum synthesis. The structure and the properties of FtsZ clearly provide it with the capacity for the cytoskeletal, perhaps motor role, necessary for "contraction" along the division plane. In addition, however, the FtsZ ring structure provides the framework for the recruitment or assembly of the ten or so membrane and cytoplasmic proteins, uniquely required for cell division in E. coli or Bacillus subtilis, some of which are required for biogenesis of the new hemispherical poles of the two daughter cells. FtsZ can polymerise into various structures, for example a single linear polymer of FtsZ monomers, called a protofilament. Protofilaments can associate laterally to form pairs (sometimes called thick filaments), bundles (ill-defined linear associations of multiple protofilaments) or thick filaments, sheets (parallel or anti-parallel two-dimensional associations of thick filaments) and tubes (anti-parallel associations of thick filaments in a circular fashion to form a tubular structure). In addition, small circles of FtsZ monomers (a short protofilament bent around to join itself, apparently head to tail) have been observed and termed mini-rings.

FtsZ is a protein of about 400 residues which is well conserved across bacterial species and which is also present in the chloroplast of plants as well as in archaebacteria . FtsZ is a homologue of eukaryotic tubulin with which it shows structural similarity.
Ras-associating domain (RA_dom)
Type: Domain

Ras proteins are signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. Ras is a prolific signalling molecule interacting with a spectrum of effector molecules and acting through more than one signalling pathway. A domain of about 100 residues, termed RA for RalGDS/AF-6 or Ras-Associating, interacts with Ras and other small GTPases. It occurs in one or two copies in a variety of signalling molecules. It can be found associated with many other domains, such as PDZ, Dilute (DIL), GEF, myosin motor, IQ, C1, C2, protein kinase, VPS9 or sterile alpha motif (SAM) .

Structurally, the RA domain of RalGDS consists of a five-stranded mixed β-sheet interrupted by a 12 residue α-helix and two additional small α-helices. The structure of the RA domain belongs to the ubiquitin α/β roll superfold and is similar to that of the RBD domain and the N-terminal third of the FERM domain . The RA domain forms a homodimer where the interdimer surface is composed of two cysteines (Cys 2 in each monomer) forming an intermolecular disulfide bond and two interacting intermolecular antiparallel β-sheets . The major interaction between Ras and RalGDS RA domain occurs between two antiparallel β-strands: β2 of Ras and β2 of RA. This interaction occurs both at the backbone as well as the side chain level .
GGDEF domain (GGDEF_dom)
Type: Domain

The GGDEF domain, which has been named after the conserved central sequence pattern GG[DE][DE]F is widespread in prokaryotes. It is typically present in multidomain proteins containing regulatory domains of signalling pathways or protein-protein or protein-ligand interaction modules, such as the response regulatory domain, the PAS/PAC domain, the HAMP domain, the GAF domain, the FHA domain or the TPR repeat. However a few single-domain proteins are also known. The GGDEF domain is involved in signal transduction and is likely to catalyse synthesis or hydrolysis of cyclic diguanylate (c-diGMP, bis(3',5')-cyclic diguanylic acid), an effector molecule that consists of two cGMP moieties bound head-to-tail .

Structural studies of PleD from Caulobacter crescentus show that this domain forms a five-stranded β-sheet surrounded by helices, similar to the catalytic core of adenylate cyclase .
Vasopressin V2 receptor (Vprsn_rcpt_V2)
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 rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present at high levels in the posterior pituitary. Vasopressin has an essential role in the control of the water content of the body, acting in the kidney to increase water and sodium absorption. In higher concentrations, vasopressin stimulates contraction of vascular smooth muscle, stimulates glycogen breakdown in the liver, induces platelet activation, and evokes release of corticotrophin from the anterior pituitary. Vasopressin and its analogues are used clinically to treat diabetes insipidus.

The V2 receptor is found in high levels in the osmoregulatory epithelia of the terminal urinary tract, where it stimulates water reabsorption. It is also present in lower levels in the endothelium and blood vessels of some species, where it induces vasodilation. In the CNS, binding sites are found in the subiculum, with lower levels in caudate-putamen and islands of Calleja. The receptor is involved in an effector pathway that forms cAMP through activation of G proteins.
GPCR, family 3, metabotropic glutamate receptor (GPCR_3_mtglu_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 .

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length . Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

The metabotropic glutamate receptors are functionally and pharmacologically distinct from the ionotropic glutamate receptors. They are coupled to G-proteins and stimulate the inositol phosphate/Ca
2+
intracellular signalling pathway . At least eight sub-types of metabotropic receptor (GRM1-8) have been identified in cloning studies. The sub-types differ in their agonist pharmacology and signal transduction pathways.
Prohibitin (Prohibitin)
Type: Family

This entry describes proteins similar to prohibitin (a lipid raft-associated integral membrane protein). Individual proteins of the SPFH (band 7) domain superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes . These microdomains, in addition to being stable scaffolds, may also be dynamic units with their own regulatory functions . Prohibitin is a mitochondrial inner-membrane protein which may act as a chaperone for the stabilization of mitochondrial proteins. Human prohibitin forms a hetero-oligomeric complex with Bap-37 (prohibitin 2, an SPFH domain carrying homologue). This complex may protect non-assembled membrane proteins against proteolysis by the m-AAA protease . Prohibitin and Bap-37 yeast homologues have been implicated in yeast longevity and in the maintenance of mitochondrial morphology. Sequence comparisons suggest that the prohibitin gene is an analogue of Cc, a Drosophila melanogaster gene that is vital for normal development .

Genes that negatively regulate proliferation inside the cell are of considerable interest because of the implications in processes such as development and cancer . Prohibitin acts as a cytoplasmic anti-proliferative protein, is widely expressed in a variety of tissues and inhibits DNA synthesis. Studies have suggested that prohibitin may be a suppressor gene and is associated with tumour development and/or progression of at least some breast cancers .