SII-SWORD/CoKE huggingface dataset:
Peptidase M13, C-terminal domain (Peptidase_M13_C)
Type: Domain

This entry represents the C-terminal domain of M13 peptidases.

This group of metallopeptidases belong to the MEROPS peptidase family M13 (neprilysin family, clan MA(E)). The M13 family includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA,

), endothelin-converting enzyme I (ECE-1,

), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. The cytoplasmic domain contains a conformationally-restrained octapeptide, which is thought to act as a stop transfer sequence that prevents proteolysis and secretion . Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity . The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH .

M13 peptidases are well-studied proteases found in a wide range of organisms including mammals and bacteria. In mammals they participate in processes such as cardiovascular development, blood-pressure regulation, nervous control of respiration, and regulation of the function of neuropeptides in the central nervous system. In bacteria they may be used for digestion of milk . The family includes eukaryotic and prokaryotic oligopeptidases, as well as some of the proteins responsible for the molecular basis of the blood group antigens e.g. Kell .
Peripherin/rom-1, conserved site (Peripherin/rom-1_CS)
Type: Conserved_site

Tetraspanins are a distinct family of cell surface proteins, containing four conserved transmembrane domains: a small outer loop (EC1), a larger outer loop (EC2), a small inner loop (IL) and short cytoplasmic tails. They contain characteristic structural features, including 4-6 conserved extracellular cysteine residues, and polar residues within transmembrane domains.

A fundamental role of tetraspanins appears to be organising other proteins into a network of multimolecular membrane microdomains, sometimes called the 'tetraspanin web'. Within this web there are primary complexes in which tetraspanins show robust, specific, and direct lateral associations with other proteins. The strong tendency of tetraspanins to associate with each other probably contributes to the assembly of a network of secondary interactions in which non-tetraspanin proteins are associated with each other via palmitoylated tetraspanins acting as linker proteins. In addition, the association of lipids, such as gangliosides and cholesterol, probably contributes to the assembly of even larger tetraspanin complexes, which have some lipid raft-like properties (e.g. resistance to solubilization in non-ionic detergents). Within the tetraspanin web, tetraspanin proteins can associate not only with integrins and other transmembrane proteins, but also with signalling enzymes such as protein kinase C and phosphatidylinositol-4 kinase. Thus, the tetraspanin web provides a mechanistic framework by which membrane protein signalling can be expanded into a lateral dimension .

The outer segments of vertebrate rod photoreceptor cells are specialised organelles that function in the transduction of light into electrical signals as part of the visual excitation process. These organelles contain thousands of closely-stacked disk membranes, which have distinctly different protein compositions in their lamellar and rim regions . Peripherin (or RDS) and rom-1 are related retinal-specific memebers of the tetraspanin family which are located at the rims of the photoreceptor disks, where they may act jointly in disk morphogenesis . Both peripherin and rom-1 form disulphide-linked homodimers. Defects in the peripherin gene (RDS) cause various human diseases such as autosomal dominant retinitis pigmentosa, autosomal dominant punctata albescens and butterfly-shaped pigment dystrophy. In mice it causes retinopathy known as 'retinal degeneration slow' (rds). These proteins contain about 350 amino acid residues. Structurally they consist of a short cytoplasmic N-terminal domain, followed by four transmembrane segments that delimit two lumenal and one cytoplasmic loops; the C-terminal domain is cytoplasmic. The second lumenal loop is very large (about 140 amino acid residues) and contains seven conserved cysteines.
Tetraspanin/Peripherin (Tetraspanin/Peripherin)
Type: Family

Tetraspanins are a distinct family of proteins, containing four transmembrane domains: a small outer loop (EC1), a larger outer loop (EC2), a small inner loop (IL) and short cytoplasmic tails. They contain characteristic structural features, including 4-6 conserved extracellular cysteine residues, and polar residues within transmembrane domains. A fundamental role of tetraspanins appears to be organizing other proteins into a network of multimolecular membrane microdomains, sometimes called the 'tetraspanin web'.

This entry represents tetraspanin proteins. It also recognises a number of peripherins. These are related retinal-specific members of the tetraspanin family which are located at the rims of the photoreceptor disks, where they may act jointly in disk morphogenesis .
DDT domain (DDT_dom)
Type: Domain

The DDT has been named after the better characterised DNA-binding homeobox- containing proteins and the Different Transcription and chromatin remodelling factors in which it is found. It is a domain of about 60 amino acids which is exclusively associated with nuclear domains like AT-Hook, PHD finger, methyl-CpG-binding domain, bromodomain and DNA-binding homeodomain.

The DDT domain is characterised by a number of conserved aromatic and charged residues and is predicted to consist of three α helices. A DNA-binding function for the DDT domain has been proposed .
Annexin repeat (Annexin_repeat)
Type: Repeat

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .
Tetraspanin, conserved site (Tetraspanin_CS)
Type: Conserved_site

Tetraspanins are a distinct family of cell surface proteins, containing four conserved transmembrane domains: a small outer loop (EC1), a larger outer loop (EC2), a small inner loop (IL) and short cytoplasmic tails. They contain characteristic structural features, including 4-6 conserved extracellular cysteine residues, and polar residues within transmembrane domains.

A fundamental role of tetraspanins appears to be organising other proteins into a network of multimolecular membrane microdomains, sometimes called the 'tetraspanin web'. Within this web there are primary complexes in which tetraspanins show robust, specific, and direct lateral associations with other proteins. The strong tendency of tetraspanins to associate with each other probably contributes to the assembly of a network of secondary interactions in which non-tetraspanin proteins are associated with each other via palmitoylated tetraspanins acting as linker proteins. In addition, the association of lipids, such as gangliosides and cholesterol, probably contributes to the assembly of even larger tetraspanin complexes, which have some lipid raft-like properties (e.g. resistance to solubilization in non-ionic detergents). Within the tetraspanin web, tetraspanin proteins can associate not only with integrins and other transmembrane proteins, but also with signalling enzymes such as protein kinase C and phosphatidylinositol-4 kinase. Thus, the tetraspanin web provides a mechanistic framework by which membrane protein signalling can be expanded into a lateral dimension .

This entry represents a short conserved site found in many tetraspanins. It is located in a short cytoplasmic loop between the second and third transmembrane domains, and contains two conserved cyteines.
RTX, pore-forming domain (RTX_pore_form)
Type: Domain

This is a hydrophobic pore-forming domain found towards the N-terminal of RTX toxins .

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior . Four principal exotoxin secretion systems have been described. In the type II and IV secretion systems, toxins are first exported to the periplasm by way of a cleaved N-terminal signal sequence; a second set of proteins is used for extracellular transport (type II), or the C terminus of the exotoxin itself is used (type IV). Type III secretion involves at least 20 molecules that assemble into a needle; effector proteins are then translocated through this without need of a signal sequence. In the Type I system, a complete channel is formed through both membranes, and the secretion signal is carried on the C terminus of the exotoxin.

The RTX (repeats in toxin) family of cytolytic toxins belong to the Type I secretion system, and are important virulence factors in Gram-negative bacteria, such as Escherichia coli (

), Actinobacillus pleuropneumoniae (

) and Kingella kingae (

). They consist of a hydrophobic pore-forming domain at the N-terminal that harbors four putative transmembrane α-helices, a typical glycine-rich repeats segment and a C-terminal signal sequence . The glycine-rich repeats are essential for binding calcium, and are critical for the biological activity of the secreted toxins . They can be divided into two different groups, (i) hemolysins, which cause cause the lysis of erythrocytes and exhibit toxicity towards a wide range of cell types from various species; and (ii) leukotoxins, that exhibit narrow cell type and species specificity due to cell-specific binding through the beta2-integrins expressed on the cell surface of leukocytes . All RTX toxin operons exist in the order rtxCABD, RtxA protein being the structural component of the exotoxin, both RtxB and D being required for its export from the bacterial cell; RtxC is an acyl-carrier-protein-dependent acyl-modification enzyme, required to convert RtxA to its active form .

Escherichia coli haemolysin (HlyA) is often quoted as the model for RTX toxins. Recent work on its relative rtxC gene product HlyC has revealed that it provides the acylation aspect for post-translational modification of two internal lysine residues in the HlyA protein. To cause pathogenicity, the HlyA toxin must first bind Ca2+ ions to the set of glycine-rich repeats and then be activated by HlyC . This has been demonstrated both
in vitro
and
in vivo
.
Cytochrome b5, heme-binding site (Cyt_B5_heme-BS)
Type: Binding_site

Cytochromes b5 are ubiquitous electron transport proteins found in animals, plants and yeasts . The microsomal and mitochondrial variants are membrane-bound, while those from erythrocytes and other animal tissues are water-soluble .

The 3D structure of bovine cyt b5 is known, the fold belonging to the α+β class, with 5 strands and 5 short helices forming a framework for supporting a central haem group . The cytochrome b5 domain is similar to that of a number of oxidoreductases, such as plant and fungal nitrate reductases, sulphite oxidase, yeast flavocytochrome b2 (L-lactate dehydrogenase) and plant cyt b5/acyl lipid desaturase fusion protein.

This conserved site includes the first of the two histidine heme ligands, which are found in the heme-binding domain of cytochrome b5 family.
Cytochrome c oxidase, subunit VIa, conserved site (Cyt_c_oxidase_su6a_CS)
Type: Conserved_site

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain complex and is involved in the transfer of electrons from cytochrome c to oxygen . In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane.

In eukaryotes, in addition to the three large subunits, I, II and III, that form the catalytic centre of the enzyme complex, there are a variable number of small polypeptidic subunits . One of these subunits is known as VIa in vertebrates and fungi. Mammals have two tissue-specific isoforms of VIa, a liver and a heart form. Only one form is found in fish .

This conserved signature pattern for cytochrome c oxidase subunit VIa is located in the C-terminal region.
3-dehydroquinate dehydratase, active site (3-dehydroquinate_DH_AS)
Type: Active_site

3-dehydroquinate dehydratase (

), or dehydroquinase, catalyzes the conversion of 3-dehydroquinate into 3-dehydroshikimate. It is the third step in the shikimate pathway for the biosynthesis of aromatic amino acids from chorismate. Two classes of dehydroquinases exist, known as types I and II.

The best studied type I enzyme is from Escherichia coli (gene aroD) and related bacteria where it is a homodimeric protein. In fungi, dehydroquinase is part of a multifunctional enzyme which catalyzes five consecutive steps in the shikimate pathway. This conserved signature pattern contains the histidine that is involved in the catalytic mechanism .
Dehydroquinase, class II, conserved site (DHquinase_II_CS)
Type: Conserved_site

3-dehydroquinate dehydratase (

), or dehydroquinase, catalyzes the conversion of 3-dehydroquinate into 3-dehydroshikimate. It is the third step in the shikimate pathway for the biosynthesis of aromatic amino acids from chorismate. Two classes of dehydroquinases exist, known as types I and II. Class-II enzymes are homododecameric enzymes of about 17kDa. They are found in some bacteria such as actinomycetales and some fungi where they act in a catabolic pathway that allows the use of quinic acid as a carbon source. This conserved signature pattern is located in the N-terminal region.
Diaminopimelate epimerase, active site (DAP_epimerase_AS)
Type: Active_site

Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids -lysine, threonine, methionine and isoleucine -in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see .

The lysine/diaminopimelic acid branch of the aspartate pathway produces the essential amino acid lysine via the intermediate meso-diaminopimelic acid (meso-DAP), which is also a vital cell wall component in Gram-negative bacteria . The production of dihydropicolinate from aspartate-semialdehyde controls flux into the lysine/diaminopimelic acid pathway. Three variants of this pathway exist, differing in how tetrahydropicolinate (formed by reduction of dihydropicolinate) is metabolised to meso-DAP. One variant, the most commonly found one in archaea and bacteria, uses primarily succinyl intermediates, while a second variant, found only in Bacillus, utilises primarily acetyl intermediates. In the third variant, found in some Gram-positive bacteria, a dehydrogenase converts tetrahydropicolinate directly to meso-DAP. In all variants meso-DAP is subsequently converted to lysine by a decarboxylase, or, in Gram-negative bacteria, assimilated into the cell wall. Evidence exists that a fourth, currently unknown, variant of this pathway may function in plants .

This entry represents diaminopimelate epimerase (

), which catalyses the isomerisation of L,L-dimaminopimelate to meso-DAP in the biosynthetic pathway leading from aspartate to lysine. It is a member of the broader family of PLP-independent amino acid racemases. This enzyme is a monomeric protein of about 30kDa consisting of two domains which are homologus in structure though they share little sequence similarity . Each domain consists of mixed β-sheets which fold into a barrel around the central helix. The active site cleft is formed from both domains and contains two conserved cysteines thought to function as the acid and base in the catalytic reaction . Other PLP-independent racemases such as glutamate racemase have been shown to share a similar structure and mechanism of catalysis.

This signature pattern covers a region surrounding the first of the two active site cysteines.
Hemolysin-type calcium-binding conserved site (Hemolysin-typ_Ca-bd_CS)
Type: Conserved_site

Gram-negative bacteria produce a number of proteins that are secreted into the growth medium by a mechanism by the type I secretion system that does not require a cleaved N-terminal signal sequence. These proteins, while having different functions, share two properties: they bind calcium and they contain a multiple tandem repeat of a nonapeptide . The nonapeptide is found in a group of bacterial exported proteins that includes haemolysin, cyclolysin, leukotoxin and metallopeptidases belonging to MEROPS peptidase family M10 (clan MA(M)), subfamily 10B (serralysin).

It has been suggested that the internally repeated domain of haemolysin may be involved in Ca-mediated binding to erythrocytes. It has been shown that such a domain is involved in the binding of calcium ions in a parallel β roll structure .
Cellulose synthase BcsB, bacterial (Cell_synthase_bac)
Type: Family

An operon encoding 4 proteins required for bacterial cellulose biosynthesis (bcs) in Acetobacter xylinus (Gluconacetobacter xylinus) has been isolated via genetic complementation with strains lacking cellulose synthase activity . Nucleotide sequence analysis showed the cellulose synthase operon to consist of 4 genes, designated bcsA, bcsB, bcsC and bcsD, all of which are required for maximal bacterial cellulose synthesis in A. xylinum.

The calculated molecular mass of the protein encoded by bcsB is 85.3kDa . BcsB encodes the catalytic subunit of cellulose synthase. The protein polymerises uridine 5'-diphosphate glucose to cellulose: UDP-glucose + (1,4-beta-D-glucosyl)(N) = UDP + (1,4-beta-D-glucosyl)(N+1). The enzyme is specifically activated by the nucleotide cyclic diguanylic acid. Sequence analysis suggests that BcsB contains several transmembrane (TM) domains, and shares a high degree of similarity with Escherichia coli YhjN.
Rabaptin coiled-coil domain (Rabaptin_CC)
Type: Domain

Regeneration of injured axons at neuromuscular junctions has been assumed to be regulated by extra-cellular factors that promote neurite outgrowth. A novel neurite outgrowth factor from chick denervated skeletal muscle has been cloned and characterised. The protein, termed neurocrescin (rabaptin), has been shown to be secreted in an activity-dependent fashion .

Rabaptin is a 100kDa coiled-coil protein that interacts with the GTP form of the small GTPase Rab5, a potent regulator of endocytic transport . It is mainly cytosolic, but a fraction co-localises with Rab5 to early endosomes. Rab5 recruits rabaptin-5 to purified early endosomes in a GTP-dependent manner, demonstrating functional similarities with other members of the Ras superfamily. Immunodepletion of rabaptin-5 from cytosol strongly inhibits Rab5-dependent early endosome fusion. Thus, rabaptin-5 is a Rab effector required for membrane docking and fusion.
Tuberin-type domain (Tuberin-type_domain)
Type: Domain

Initiation of eukaryotic mRNA transcription requires melting of promoter DNA with the help of the general transcription factors TFIIE and TFIIH. In higher eukaryotes, the general transcription factor TFIIE consists of two subunits: the large alpha subunit (

) and the small beta (

). TFIIE beta has been found to bind to the region where the promoter starts to open to be single-stranded upon transcription initiation by RNA polymerase II. The approximately 120-residue central core domain of TFIIE beta plays a role in double-stranded DNA binding of TFIIE .

The TFIIE β-central core DNA-binding domain consists of three helices with a β-hairpin at the C terminus, resembling the winged helix proteins. It shows a novel double-stranded DNA-binding activity where the DNA-binding surface locates on the opposite side to the previously reported winged helix motif by forming a positively charged furrow .

This domain is found in Tuberin proteins.
tRNA-dihydrouridine synthase, conserved site (tRNA_hU_synthase_CS)
Type: Conserved_site

Members of this family catalyse the reduction of the 5,6-double bond of a uridine residue on tRNA. Dihydrouridine modification of tRNA is widely observed in prokaryotes and eukaryotes, and also in some archaea. Most dihydrouridines are found in the D loop of tRNAs. The role of dihydrouridine in tRNA is currently unknown, but may increase conformational flexibility of the tRNA. It is likely that different family members have different substrate specificities, which may overlap. Dus 1 (

) from Saccharomyces cerevisiae (Baker's yeast) acts on pre-tRNA-Phe, while Dus 2 (

) acts on pre-tRNA-Tyr and pre-tRNA-Leu. Dus 1 is active as a single subunit, requiring NADPH or NADH, and is stimulated by the presence of FAD . Some family members may be targeted to the mitochondria and even have a role in mitochondria .
Di-trans-poly-cis-decaprenylcistransferase-like, conserved site (UPP_synth-like_CS)
Type: Conserved_site

Synonym(s): Di-trans-poly-cis-undecaprenyl-diphosphate synthase, Undecaprenyl pyrophosphate synthetase, Undecaprenyl pyrophosphate synthase, UPP synthetase

Di-trans-poly-cis-decaprenylcistransferase (

) (UPP synthetase) generates undecaprenyl pyrophosphate (UPP) from isopentenyl pyrophosphate (IPP) . This bacterial enzyme is also found in archaebacteria and in a number of uncharacterised proteins including some from yeasts.

This conserved pattern is found towards the C-terminal region in many of the proteins in this entry. The proteins are of about 26 to 40kDa whose central region is well conserved. This pattern also hits related enzymes such as dehydrodolichyl diphosphate synthase.