SII-SWORD/CoKE huggingface dataset:
SH2 domain (SH2)
Type: Domain

The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps . Similar sequences were later found in many other intracellular signal-transducing proteins . SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner . They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates.

The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins .
Neurohypophysial hormone (Neurhyp_horm)
Type: Family

Oxytocin and vasopressin are nine-residue, structurally and functionally related neurohypophysial peptide hormones. Oxytocin mediates contraction of the smooth muscle of the uterus and mammary gland, while vasopressin has antidiuretic action on the kidney, and mediates vasoconstriction of the peripheral vessels . In common with most active peptides, both hormones are synthesised as larger protein precursors that are enzymatically converted to their mature forms. Members of this family are found in birds, fish, reptiles and amphibians (mesotocin, isotocin, valitocin, glumitocin, aspargtocin, vasotocin, seritocin, asvatocin, phasvatocin), in worms (annetocin, nematocin), octopi (cephalotocin), Locusta migratoria (Migratory locust) (locupressin or neuropeptide F1/F2) and in molluscs (conopressins G and S) .
Matrix protein, N-terminal domain (Matrix_Paramyxo_N)
Type: Domain

This entry represents the N-terminal domain found in a variety of paramyxoviruses such as Morbillivirus, paramyxovirus, pneumovirus M proteins. The N-terminal domain of the NDV matrix protein adopts a β-sandwich fold in which the β-strands in the opposing β-sheets are approximately orthogonal to each other. Several α-helices are situated mostly on the surface of this β-sandwich domain. The N-terminal domain is connected to a C-terminal domain with similar fold via a 16 amino acid linker. The two domains are related by an approximate fourfold rotation axis coincident with the twofold axis of the matrix protein dimer. The matrix protein dimer represents the physiologically relevant assembly unit. The N-terminal domain contributes to the highly positively charged surface that faces the viral membrane, enabling association with the negatively charged membrane .

The matrix protein plays a crucial role in virus assembly, and interacts with the RNP complex as well as with the viral membrane. It is found in Morbillivirus, Paramyxovirus, Pneumovirus.
Bacterial general secretion pathway protein G-type pilin (Bac_GSPG_pilin)
Type: Family

The general (type II) secretion pathway (GSP) within Gram-negative bacteria is a signal sequence-dependent process responsible for protein export , including virulence factors. The process has two stages, exoproteins are first translocated across the inner membrane by the general signal-dependent export pathway (GEP), and then across the outer membrane by a species-specific accessory mechanism. One of the proteins involved in the GSP is termed general secretion pathway protein G (GSPG). This protein shares several sequence similarities with bacterial fimbrial protein, or pilin, the major structural protein of pili . Pili are polar flexible filamentous adhesions ~2500 nm in length, and diameter ~5.4 nm. Fimbrial and GSPG proteins share the following characteristics; a methylated, hydrophobic N-terminal residue; a hydrophobic leader peptide of 5-10 residues, terminating with glycine; glutamate as the fifth residue of the mature sequence; and a highly hydrophobic N-terminal. This system is homologous to the type IV pilus biogenesis and includes different proteins, termed psudopilins, which are structurally homologous to the type IV pilins .
G protein-coupled receptor 3 (GPR3)
Type: Family

G protein-coupled receptor 12 (GPR12) was initially isolated from a rat pituitary library, and is found in discrete regions of the brain, pituitary and testis, but is absent in other tissues . Three human homologues (GPR12, GPR6 and GPR3) have also been isolated . The 3 genes have been localised to human chromosomal regions 13q12, 6q21
and 1p34.3-p36.1 respectively.

This entry represents the G protein-coupled receptor 3. It is an orphaned receptor, with no endogenous ligand having yet been identified.
Neuropeptide Y6 receptor (NeuroY6_rcpt)
Type: Family

Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat , facilitation of learning and memory via the modulation of hippocampal activity , inhibition of anxiety , presynaptic inhibition of neurotransmitter release in the CNS and periphery , and modulation of circadian rhythm . In the periphery, NPY stimulates vascular smooth muscle contraction , modulates the release of pituitary hormones , pain transmission , inhibition of insulin release and modulation of renal function . NPY has also been implicated in the pathophysiology of hypertension , congestive heart failure and appetite regulation and controlling epileptic seizures . Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue . These include inhibition of Ca2+ channels, such as in neurones , and activation and inhibition of K+ channels, such as in cardiomyocytes and vascular smooth muscle cells .

The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide . There are five pharmacologically distinct neuropeptide Y receptor subtypes ; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6).

This entry represents the neuropeptide Y6 receptor, which shares 60% sequence identity with the Y1 receptor. Its pharmacology resembles that of the Y1 receptor and is distinct from that described for Y2, Y3 and Y4 receptors . In mice, the Y6 receptor is expressed within discrete regions of the hypothalamus, including the suprachiasmatic nucleus, anterior hypothalamus, bed nucleus stria terminalis, and the ventromedial nucleus, with no localisation apparent elsewhere in the brain; and in the testis. The absence of this protein leads to major reduction in bone mass without modifying bone length .
Replication protein (Rep)
Type: Family

Replication proteins (rep) are involved in plasmid replication. The Rep protein binds to the plasmid DNA and nicks it at the double strand origin (dso) of replication. The 3'-hydroxyl end created is extended by the host DNA replicase, and the 5' end is displaced during synthesis. At the end of one replication round, Rep introduces a second single stranded break at the dso and ligates the ssDNA extremities generating one double-stranded plasmid and one circular ssDNA form. Complementary strand synthesis of the circular ssDNA is usually initiated at the single-stranded origin by the host RNA polymerase .
Innexin (Innexin)
Type: Family

This entry includes pannexins from vertebrates and innexins from invertebrate . Gap junctions are composed of membrane proteins, which form a channel permeable for ions and small molecules connecting cytoplasm of adjacent cells. Although gap junctions provide similar functions in all multicellular organisms, until recently it was believed that vertebrates and invertebrates use unrelated proteins for this purpose. While the connexins family of gap junction proteins is well- characterised in vertebrates, no homologues have been found in invertebrates. In turn, gap junction molecules with no sequence homology to connexins have been identified in insects and nematodes. It has been suggested that these proteins are specific invertebrate gap junctions, and they were thus named innexins (invertebrate analog of connexins) . As innexin homologues were recently identified in other taxonomic groups including vertebrates, indicating their ubiquitous distribution in the animal kingdom, they were called pannexins (from the Latin pan-all, throughout, and nexus-connection, bond) .

Genomes of vertebrates carry probably a conserved set of 3 pannexin paralogs (PANX1, PANX2 and PANX3). Invertebrate genomes may contain more than a dozen pannexin (innexin) genes. Vinnexins, viral homologues of pannexins/innexins, were identified in Polydnaviruses that occur in obligate symbiotic associations with parasitoid wasps. It was suggested that virally encoded vinnexin proteins may function to alter gap junction proteins in infected host cells, possibly modifying cell-cell communication during encapsulation responses in parasitized insects . Structurally pannexins are simillar to connexins. Both types of protein consist of a cytoplasmic N-terminal domain, followed by four transmembrane segments that delimit two extracellular and one cytoplasmic loops; the C- terminal domain is cytoplasmic.
Stress-induced protein SRP1/TIP1 (SRP1_TIP1)
Type: Family

It has recently been shown that three yeast proteins, two of which are known to be induced by various stress conditions, are structurally related and are probably part of a larger family. These proteins include cold-shock inducible protein TIR1 (also known as serine-rich protein 1, SRP1), which is induced by glucose and cold shock ; temperature-shock inducible protein 1 (SRP2) ; seripauperins, which are closely related protein of about 13kDa (120 to 124 residues) and are generally encoded at the extremity of yeast chromosomes (eg. PAU1, PAU2, PAU3, PAU4, PAU5, PAU6, YBR301w, YGL261c, YGR294w, YHL046c, YIL176c, YIR041w and YKL224c) ; and hypothetical proteins YIL011w, YJR150c and YJR151c. These proteins all seem to start with a putative signal sequence followed by a conserved domain of about 90 residues. In TIR1, TIR2, TIP1, YIL011w, YJR150c and YJR151c, this domain is followed by a repetitive serine and alanine rich region absent in the other members of this family.
Peptidase M24 (Pept_M24)
Type: Domain

This entry contains proteins that belong to MEROPS peptidase family M24 (clan MG), which share a common structural-fold, the "pita-bread" fold. The fold contains both α helices and an anti-parallel β sheet within two structurally similar domains that are thought to be derived from an ancient gene duplication. The active site, where conserved, is located between the two domains. The fold is common to methionine aminopeptidase (

), aminopeptidase P (

), prolidase (

), agropine synthase and creatinase (

). Though many of these peptidases require a divalent cation, creatinase is not a metal-dependent enzyme .
Muscarinic acetylcholine receptor family (Musac_Ach_rcpt)
Type: Family

Muscarinic acetylcholine receptors are members of rhodopsin-like G-protein coupled receptor family. They play several important roles; they mediate many of the effects of acetylcholine in the central and peripheral nervous system and modulate a variety of physiological functions, such as airway, eye and intestinal smooth muscle contraction, heart rate and glandular secretions. The receptors have a widespread tissue distribution and are a major drug target in human disease. They may be effective therapeutic targets in Alzheimer's disease, schizophrenia, Parkinson's disease and chronic obstructive pulmonary disease .

This entry represents the muscarinic acetylcholine receptor family.
Clathrin light chain (Clathrin_L-chain)
Type: Family

Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport . Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors .

Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion . The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase . Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process . The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins .

This entry represents clathrin light chains, which are more divergent in sequence than the heavy chains . In higher eukaryotes, two genes encode distinct but related light chains, each of which can yield two separate forms via alternative splicing. In yeast there is a single light chain whose sequence is only distantly related to that of higher eukaryotes. Clathrin light chains have a conserved acidic N-terminal domain, a central coiled-coil domain and a conserved C-terminal domain.
Cholinesterase (Cholinesterase)
Type: Family

Cholinesterase enzymes are members of the broader alpha/beta hydrolase family and can be dividied into two distinct groups: those that catalyse the hydrolysis of acetylcholine to choline and acetate (acetylcholinesterases

)

acetylcholine + H
2
O ->choline + acetate

and those that catalyse the conversion of other acylcholines to a choline and a weak acid (cholinesterases

)

an acylcholine + H
2
O ->choline + a carboxylate

Acetylcholinesterase also acts on a variety of acetic esters and catalyses transacetylations. It is the most intensively studied of the cholinesterase enzymes due to its key physiological role in the turnover of the neurotransmitter acylcholine . This enzyme is found in, or attached to, cellular or basement membranes of presynaptic cholinergic neurons and postsynaptic cholinoceptive cells within the neuromuscular junction. Signal transmission at the neuromuscular junction involves the release of acylcholine, its interaction with the acycholine receptor and hydrolysis, all occuring in a period of a few milliseconds. Rapid hydrolysis of the newly released aceytlcholine is vital in order to prevent continuous firing of the nerve impulses . Consistent with its role in this process, acetylcholinesterase has an unusually high turnover number, ensuring that acetylcholine is broken down quickly. There is evidence to suggest that acetylcholinesterase has additional important roles including involvement in neuronal adhesion, the formation of Alzheimer fibrils, and neurite growth .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Acetylcholinesterase (

) belongs to the Yt blood group system and is associated with Yt(a/b) antigen.
MAM domain (MAM_dom)
Type: Domain

MAM is an acronym derived from meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu. The MAM domain consists of approximately 170 amino acids. It occurs in several cell surface proteins and is likely to have an adhesive function . The domain has been shown to play a role in homodimerization of protein-tyrosine phosphatase mu and appears to help determine the specificity of these interactions. It contains four conserved cysteines which probably form two disulfide bridges. It has been reported that certain cysteine mutations in the MAM domain of murine meprin A result in the formation of monomeric meprin, which has altered stability and activity . This indicates that these domain-domain interactions are critical for structure and function of the enzyme.

Proteins containing this domain are listed below.

Meprin. This cell surface glycoprotein contains a zinc-metalloprotease domain capable of degrading a variety of polypeptides. Meprin is composed of two structurally related subunits (alpha and beta) that form homo- or heterotetramers by the non-covalent association of two disulfide-linked dimers. In both subunits, the MAM domain is located after the catalytic domain. It has also been shown that the MAM domain of meprins is necessary for correct folding and transport through the secretory pathway .

Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that function during the formation of certain neuronal circuits. The sequence contains 2 CUB domains and a MAM domain.

Receptor-like tyrosine protein phosphatases Mu, Kappa and PCP-2 (

). These PTPases have an extracellular region which consists of a MAM domain followed by an Ig-like domain and four fibronectin-type III domains.

Vertebrate enteropeptidase (

), a type II membrane protein of the intestinal brush border, which activates trypsinogen. It consists at least of a catalytic light chain and a multidomain heavy chain which has 2 LDL receptor class A domains, a MAM domain, a SRCR domain and a CUB domain.

Apical endosomal glycoprotein from rat, a protein probably involved in the sorting and selective transport of receptors and ligands across polarized epithelia. This protein contains 6 MAM domains.

Xenopus laevis thyroid hormone induced protein B. This protein contains 4 MAM domains.

Pig zonadhesin, a protein that binds in a species-specific manner to the zona pellucida of the egg.
Ribonuclease III domain (RNase_III_dom)
Type: Domain

This domain is found in eukaryotic, bacterial and archeal ribonuclease III (RNAse III) proteins. RNAse III is a double stranded RNA-specific endonuclease . Prokaryotic RNAse III is important in post-transcriptional control of mRNA stability and translational efficiency. It is involved in the processing of ribosomal RNA precursors. Prokaryotic RNAse III also plays a role in the maturation of tRNA precursors and in the processing of phage and plasmid transcripts. Eukaryotic RNase III's participate (through direct cleavage) in rRNA processing, in processing of small nucleolar RNAs (snoRNAs) and snRNA's (components of the spliceosome). In eukaryotes RNase III or RNaseIII like enzymes such as Dicer are involved in RNAi (RNA interference) and miRNA (micro-RNA) gene silencing .
Glycoside hydrolase family 10 domain (GH10_dom)
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.

Glycoside hydrolase family 10

comprises enzymes with a number of known activities; xylanase (

); endo-1,3-beta-xylanase (

); cellobiohydrolase (

). These enzymes were formerly known as cellulase family F.

The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases (

), cellobiohydrolases (

) (exoglucanases), or xylanases (

) . Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family F or as the glycosyl hydrolases family 10 .

The overall structure of the GH10 domain corresponds to an eightfold α/β-barrel (TIM-barrel) with a typical deep groove in the centre, allowing an 'endo' type of action on the large polysaccharide backbone , .
DNA polymerase III, beta sliding clamp (DNA_polIII_beta)
Type: Family

DNA polymerase III is a complex, multichain holoenzyme responsible for most of the replicative synthesis in bacteria . It functions by adding nucleotide triphosphate (dNTP) residues to the 5'-end of a growing DNA chain, using a complementary DNA as template. The elongation factor beta-clamp, also called beta subunit, is part of the DNA polymerase III holoenzyme. However, beta-clamp is not attached to polymerase III permanently like the other subunits. It is loaded on the DNA, by clamp loader, a subunit of DNA Pol III .

The beta clamp forms a ring shaped dimer that encircles dsDNA (sliding clamp) in bacteria. The bacterial beta clamp is a homodimer; each monomer consists of three globular domains to yield a six-domain ring . It is structurally similar to the trimeric ring formed by proliferating cell nuclear antigen (PCNA) (found in eukaryotes and archaea) and the processivity factor (found in bacteriophages T4 and RB69) . This structural correspondence further substantiates the mechanistic connection between eukaryotic and prokaryotic DNA replication that has been suggested on biochemical grounds.
Chitin-binding, type 1 (Chitin-bd_1)
Type: Domain

A number of plant and fungal proteins that bind N-acetylglucosamine (e.g. solanaceous lectins of tomato and potato, plant endochitinases, the wound-induced proteins: hevein, win1 and win2, and the Kluyveromyces lactis killer toxin alpha subunit) contain this domain . The domain may occur in one or more copies and is thought to be involved in recognition or binding of chitin subunits . In chitinases, as well as in the potato wound-induced proteins, the 43-residue domain directly follows the signal sequence and is therefore at the N terminus of the mature protein; in the killer toxin alpha subunit it is located in the central section of the protein.