SII-SWORD/CoKE huggingface dataset:
Sterol biosynthesis ERG24/DHCR-like (ERG24_DHCR-like)
Type: Family

This entry represents a group of enzymes involved in the steroid biosynthetic pathway, including 7-dehydrocholesterol reductase and Delta(14)-sterol reductase LBR (lamin B receptor) from animals , Delta(14)-sterol reductase from fungi and plants and Delta(24(24(1)))-sterol reductase from yeast . These proteins act by reducing double bonds in precursors of ergosterol, are highly hydrophobic and seem to contain seven or eight transmembrane regions.
Flagellar motor switch FliN/Type III secretion HrcQb (FliN_T3SS_HrcQb)
Type: Family

The flagellar motor switch in Escherichia coli and Salmonella typhimurium regulates the direction of flagellar rotation and hence controls swimming behaviour. The switch is a complex apparatus that responds to signals transduced by the chemotaxis sensory signalling system during chemotactic behaviour . The switch complex comprises at least three proteins - FliG, FliM and FliN. It has been shown that FliG interacts with FliM, FliM interacts with itself, and FliM interacts with FliN . The proteins are not particularly hydrophobic and may be peripheral to the membrane, possibly mounted on the basal body M ring .

This entry represents the flagellar motor switch proteins FliN and FliY, and proteins related with type III secretion system such as hrcQb and SsaQ. Members of this group of proteins are mainly found in bacteria.
Glycosyltransferase 2-like (Glyco_trans_2-like)
Type: Domain

This domain is found in a diverse family of glycosyl transferases that transfer the sugar from UDP-glucose, UDP-N-acetyl-galactosamine, GDP-mannose or CDP-abequose, to a range of substrates including cellulose, dolichol phosphate and teichoic acids .

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.
HddA/FKP (HddA/FKP)
Type: Family

This entry includes D-glycero-alpha-D-manno-heptose 7-phosphate kinase (HddA) from Mycobacterium tuberculosis and its orthologue L-fucokinase/L-fucose-1-P guanylyltransferase (FKP) from Bacteroides fragilis .

HddA catalyses the phosphorylation of D-glycero-alpha-D-manno-heptose 7-phosphate at the C-1 position to form D-glycero-alpha-D-manno-heptose 1,7-bisphosphate . FKP is a bifunctional enzyme involved in the salvage pathway of GDP-fucose synthesis. It catalyses two successive reactions, the ATP-dependent phosphorylation of L-fucose to L-fucose 1-phosphate, and its guanylylation to GDP-L-fucose. GDP-fucose is an important fucose donor in the process of fucosylated oligosaccharides formation .
DNA helicase E1, C-terminal, Papillomavirus (PPV_DNA_helicase_E1_C)
Type: Domain

Papillomaviruses (PPV) are a large family of DNA tumour viruses which give rise to warts in their host species. The helicase E1 protein is an ATP-dependent DNA helicase required for initiation of viral DNA replication . It forms a complex with the viral E2 protein, which is a site-specific DNA-binding transcriptional activator. The E1-E2 complex binds to the replication origin which contains binding sites for both proteins .

The E1 protein is a 70kDa polypeptide with a central DNA-binding domain and a C-terminal ATPase/helicase domain. It binds specific 18 bp DNA sequences at the origin of replication, melts the DNA duplex and functions as a 3' to 5' helicase . In addition to E2 it also interacts with DNA polymerase alpha and replication protein A to effect DNA replication. The DNA-binding domain forms a five-stranded antiparallel β sheet bordered by four loosely packed α helices on one side and two tightly packed helices on the other . Two structural modules within this domain, an extended loop and a helix, contain conserved residues and are critical for DNA binding. In solution E1 is a monomer, but binds DNA as a dimer. Recruitment of more E1 subunits to the complex leads to melting of the origin and ultimately to the formation of an E1 hexamer with helicase activity .

The entry represents the ATPase domain found at the C-terminal of E1.
Pesticidal crystal protein, domain II (Pest_cryst_dom_II)
Type: Domain

This entry represents the conserved second domain of the toxic core.

The crystal proteins of Bacillus thuringiensis have been extensively studied because of their pesticidal properties and their high natural levels of production . When an insect ingests these proteins, they are activated by proteolytic cleavage. The N terminus is cleaved in all of the proteins and a C-terminal extension is cleaved in some members. Once activated, the endotoxin binds to the gut epithelium and causes cell lysis by the formation of cation-selective channels, which leads to death. The activated region of the toxin is composed of three distinct structural domains: an N-terminal helical bundle domain (

) involved in membrane insertion and pore formation; a β-sheet central domain involved in receptor binding; and a C-terminal β-sandwich domain (

) that interacts with the N-terminal domain to form a channel .

This entry represents the central β-sheet domain, which consists of three four-stranded β-sheets, each with a Greek key fold, with internal pseudo threefold symmetry. Thus, it acts as a receptor binding β-prism, binding to insect-specific receptors of gut epithelial cells .
FKBP-type peptidyl-prolyl cis-trans isomerase domain (PPIase_FKBP_dom)
Type: Domain

FKBP-type peptidylprolyl isomerases (

) in vertebrates, are receptors for the two immunosuppressants, FK506 and rapamycin. The drugs inhibit T cell proliferation by arresting two distinct cytoplasmic signal transmission pathways. Peptidylprolyl isomerases accelerate protein folding by catalysing the cis-trans isomerisation of proline imidic peptide bonds in oligopeptides. These proteins are found in a variety of organisms .

This entry represents a domain found in FKBP-type peptidylprolyl isomerases.
Citron homology (CNH) domain (CNH_dom)
Type: Domain

Based on sequence similarities a domain of homology has been identified in the following proteins :

Citron and Citron kinase. These two proteins interact with the GTP-bound forms of the small GTPases Rho and Rac but not with Cdc42.

Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCKalpha). This serine/threonine kinase interacts with the GTP-bound form of the small GTPase Cdc42 and to a lesser extent with that of Rac.

NCK Interacting Kinase (NIK), a serine/threonine protein kinase.

ROM-1 and ROM-2, from yeast. These proteins are GDP/GTP exchange proteins (GEPs) for the small GTP binding protein Rho1.

This domain, called the citron homology domain (CNH), is often found after cysteine rich and pleckstrin homology (PH) domains at the C-terminal end of a group of eukaryotic proteins. It is thought to act as a regulatory domain and could be involved in macromolecular interactions . Its structure has been solved in Rho guanyl nucleotide exchange factor (Rom2) from Neosartorya fumigata (Aspergillus fumigatus,

), where it shows a canonical β-propeller fold containing seven blades connected by small loops and arranged in a circular fashion .
Interleukin-7 (IL-7)
Type: Family

This entry represents interleukin-7 (IL7), it is a hematopoietic growth factor produced by bone marrow stromal cells. It promotes growth of B- and T-cell precursors and functions with IL2 in the activation of mature T-cells . IL-7 and IL-7Ralpha bind the gamma-c receptor forming a complex required for the development and homeostasis of T and B cells . Interleukin-7 and Interleukin-9 belong to the same larger family.
Probable peptidoglycan glycosyltransferase FtsW/RodA (FtsW/RodA)
Type: Family

A number of prokaryotic integral membrane proteins involved in cell cycle processes have been found to be structurally related . These proteins include, the Escherichia coli and related bacteria cell division protein ftsW and the rod shape-determining protein rodA (or mrdB), the Bacillus subtilis stage V sporulation protein E (spoVE), the B. subtilis hypothetical proteins ywcF and ylaO and the Cyanophora paradoxa cyanelle ftsW homologue. They constitute the SEDS (shape, elongation, division and sporulation) family. SEDS proteins are thought to be peptidoglycan polymerases, functioning as cell wall synthases of the cell elongation and division machinery .
Muscarinic acetylcholine receptor M3 (Musac_Ach_M3_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 .

Muscarinic acetylcholine M3 receptors are located in smooth muscles, endocrine glands, exocrine glands, lungs, pancreas and the brain . They are found in high levels in neuronal cells of the CNS, their distribution largely overlapping with that of M1 and M4 receptor subtypes. The primary role of M3 muscarinic receptors is contraction of smooth muscle, particularly of airway, ileum, iris and bladder . The receptors are also expressed on pancreatic beta-cells and in areas of the brain where they influence insulin secretion , indicating that M3 receptors might be an important target for understanding the mechanisms of type 2 diabetes mellitus. M3 receptors are also involved in exocrine secretion, particularly of saliva .
Somatostatin receptor 5 (Somatstn_rcpt_5)
Type: Family

Somatostatin (SST), also known as somatotropin release-inhibiting factor (SRIF), is a hypothalamic hormone, a pancreatic hormone, and a central and peripheral neurotransmitter. Somatostatin has a wide distribution throughout the central nervous system (CNS) as well as in peripheral tissues, for example in the pituitary, pancreas and stomach. The various actions of somatostatin are mediated by a family of rhodopsin-like G protein-coupled receptors, which comprise of five distinct subtypes: Somatostatin receptor 1 (SSTR1), Somatostatin receptor 2 (SSTR2), Somatostatin receptor 3 (SSTR3), Somatostatin receptor 4 (SSTR4) and Somatostatin receptor 5 (SSTR5) . These subtypes are widely expressed in many tissues , and frequently multiple subtypes coexist in the same cell . The somatostatin receptor subtypes also share common signalling pathways, such as the inhibition of adenylyl cyclase , activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K+ channels (SSTR2, SSTR3, SSTR4, SSTR5) , to voltage-dependent Ca2+ channels (SSTR1, SSTR2) , to an Na+/H+ exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, SSTR2), phospholipase C (SSTR2, SSTR5), and phospholipase A2 (SSTR4) .

This entry represents SST5R. It is expressed in range of tissues including the small intestine, heart, adrenal, cerebellum, pituitary, placenta and skeletal muscle. It is also expressed in pancreatic islets , where somatostatin is a known regulator of insulin and glucagon secretion. All five human somatostatin receptors expressed in COS-7 cells have been shown to couple to activation of phosphoinositide (PI)-specific PLC-beta; and Ca2+ mobilisation via pertussis toxin-sensitive G protein(s) with an order of potency of SSTR5 >SSTR2 >SSTR3 >SSTR4 >SSTR1 .
Large-conductance mechanosensitive channel (MS_channel)
Type: Family

Mechanosensitive ion channels (MscL) play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. MscL is a protein which forms a channel organised as a homopentamer, with each subunit containing two transmembrane regions . Prokaryotes harbor a large-conductance mechanosensitive channel (gene mscL) that opens in response to stretch forces in the membrane lipid bilayer and participate in the regulation of osmotic pressure changes within the cell . MscL has a conserved domain architecture which comprises an amphipathic α-helix (S1) that lies along the cytoplasmic membrane, a highly conserved first transmembrane domain (TM1) that forms the pore constriction, a periplasmic loop, a second transmembrane domain (TM2) that faces the lipid membrane, and a linker that leads to a cytoplasmic α-helical bundle .
Bradykinin receptor B1 (Brdyknn_1_rcpt)
Type: Family

Bradykinins are a family of short, structurally similar peptides that activate sensory fibres, contract venous smooth muscle, stimulate release of cytokines, induce connective tissue proliferation and mediate endothelium-dependent vasodilation . Bradykinin antagonists are used in the treatment of inflammation, asthma, mild pain and endotoxic shock.

Bradykinin receptors are members of the seven transmembrane, rhodopsin-like G-protein coupled receptor family and are widespread in peripheral tissues. There are two bradykinins receptor subtypes: B1 and B2. It has also been proposed there could be further subtypes of the bradykinin receptor, including a tracheal B3 receptor but these, as yet have not been confirmed .

This entry represents bradykinin receptor B1, which has limited distribution in the periphery, and has not been described in the CNS, unlike the bradykinin receptor B2, which is the predominant subtype. Both B1 and B2 receptors are involved in the induction and maintenance of cytokine-induced hyperalgesia. However B1 receptors appear to play a more important role in the development of mechanical hyperalgesia . The B1 receptor is synthesized de novo following tissue injury and receptor binding leads to an increase in the cytosolic calcium ion concentration, ultimately resulting in chronic and acute inflammatory responses . In the majority of tissues, bradykinin induces activation of phosphoinositide metabolism via a pertussis-toxin-insensitive G-protein of the Gq/G11 class. It has also been reported to inhibit adenylyl cyclase and raises levels of cyclic guanosine monophosphate (cGMP) and open ion channels. B1 receptor also stimulates phospholipase A2 (PLA2) .
Tissue factor (Tissue_factor)
Type: Family

Tissue factor (TF, also known as thromboplastin) is an integral membrane glycoprotein that initiates blood coagulation by forming a complex with circulating factor VII (FVII) or VIIa (FVIIa), which it comes in contact with following damage to blood vessel walls. Calcium forms the bridge between TF and FVII, the resultant TF/FVII undergoing auto-cleavage to produce activated TF/FVIIa. This activation sets off an extracellular cascade involving sequential serine protease activations, where TF/FVIIa converts FIX to FIXa, followed by a series of reactions to finally produce fibrin, leading to fibrin deposition and the activation of platelets to form clots .
Spermidine/putrescine-binding periplasmic protein (Sperm_putr-bd)
Type: Family

Bacterial high affinity transport systems are involved in active transport of solutes across the cytoplasmic membrane. The protein components of these traffic systems include one or two transmembrane protein components, one or two membrane-associated ATP-binding proteins and a high affinity periplasmic solute-binding protein. In Gram-positive bacteria, which are surrounded by a single membrane and therefore have no periplasmic region, the equivalent proteins are bound to the membrane via an N-terminal lipid anchor. These homologue proteins do not play an integral role in the transport process per se, but probably serve as receptors to trigger or initiate translocation of the solute through the membrane by binding to external sites of the integral membrane proteins of the efflux system. In addition at least some solute-binding proteins function in the initiation of sensory transduction pathways.

The bacterial Spermidine/putrescine-binding periplasmic protein (PotD) is involved in
the polyamine transport system. It is required for the activity of the bacterial
periplasmic transport system of putrescine and spermidine . This protein has two domains connected through
two β-strands, which form a hinge at the bottom of the central cleft, and this hinge lies
and one short peptide segment .

Similar proteins with specificities for putrecine and spermidine are also included in this family, such as Putrescine-binding periplasmic protein PotF from Escherichia coli, more specifically involved in putrescine uptake and Spermidine-binding periplasmic protein SpuE from Pseudomonas aeruginosa respectively.

Putrescine/cadaverine-binding protein and Putrescine/agmatine-binding protein from P. aeruginosa also belong to this entry .
Manganese/iron superoxide dismutase (Mn/Fe_SOD)
Type: Family

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .
SRCR domain (SRCR)
Type: Domain

The scavenger receptor cysteine-rich (SRCR) domain is an ancient and highly conserved domain of about 110 residues which is found in diverse secreted and cell-surface proteins, like the type I scavenger receptor, the speract receptor, CD5/Ly-1, CD6, or complement factor I . Tandem repeats of SRCR domains are common in the membrane bound proteins. Most SRCR domains have six to eight cysteines that participate in intradomain disulfide bonds. SRCR domains have been subdivided into two groups, A and B, primarily on the differences in the spacing pattern between the cysteine residues .

Although the biochemical functions of SRCR domains have not been established with certainty, they are likely to mediate protein-protein interactions and ligand binding .

Determination of the crystal structure of the SRCR domain of M2BP reveals that the M2NP SRCR adopts a compact fold of approximate dimensions 22 x 26 x 30 Angstrom, organised around a curved six-stranded β-sheet cradling an alpha- helix .
Geminivirus AL1, replication-associated protein (Gemini_AL1_REP)
Type: Family

Geminiviruses are characterised by a genome of circular single-stranded DNA encapsidated in twinned (geminate) quasi-isometric particles, from which the group derives its name . Most geminiviruses can be divided into two subgroups on the basis of host range and/or insect vector: i.e. those that infect dicotyledenous plants and are transmitted by the same whitefly species, and those that infect monocotyledenous plants and are transmitted by different leafhopper vectors. The genomes of the whitefly-transmitted African cassava mosaic virus, Tomato golden mosaic virus (TGMV) and Bean golden mosaic virus (BGMV) possess a bipartite genome. By contrast, only a single DNA component has been identified for the leafhopper-transmitted Maize streak virus (MSV) and Wheat dwarf virus (WDV) . Beet curly top virus (BCTV), and Tobacco yellow dwarf virus belong to a third possible subgroup. Like MSV and WDV, BCTV is transmitted by a specific leafhopper species, yet like the whitefly-transmitted geminiviruses it has a host range confined to dicotyledenous plants.

Sequence comparison of the whitefly-transmitted Squash leaf curl virus (SqLCV) and Tomato yellow leaf curl virus (TYLCV) with the genomic components of TGMV and BGMV reveals a close evolutionary relationship . Amino acid sequence alignments of Potato yellow mosaic virus (PYMV) proteins with those encoded by other geminiviruses show that PYMV is closely related to geminiviruses isolated from the New World, especially in the putative coat protein gene regions . Comparison of MSV DNA-encoded proteins with those of other geminiviruses infecting monocotyledonous plants, including Panicum streak virus and Miscanthus streak virus (MiSV) , reveal high levels of similarity.
Phosphoinositide phospholipase C family (PI-PLC_fam)
Type: Family

This entry represents phosphoinositol-specific phospholipase C (PLC) from eukaryotes. Proteins in this entry include PLC-beta, gamma, delta, epsilon, eta, zeta and inactive phospholipase C-like protein 2 (PLC-L2).

Phosphoinositol-specific phospholipase C (PLC; (

) plays an important role in signal transduction processes , mediating the cellular actions of a variety of hormones, neurotransmitters and growth factors. Upon agonist-dependent activation, PLC catalyses the hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate (PIP2), generating the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds specific intracellular receptors to trigger Ca
2+
mobilisation, while DAG mediates activation of a family of protein kinase C isozymes. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins . Based on molecular size, immunoreactivity and amino acid sequence, several subtypes have been classified. Overall, sequence identity between sub-types is low, yet all isoforms share a split TIM barrel containing two conserved domains, designated X and Y .
Membrane-bound transcription factor site-2 protease (MBTPS2)
Type: Family

This entry represents the membrane-bound transcription factor site-2 protease (MBTPS2, also known as S2P) .

MBTPS2 is a membrane-embedded zinc metalloprotease that activates signaling proteins involved in sterol control of transcription and ER stress response . It cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Its known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6 .