SII-SWORD/CoKE huggingface dataset:
Aspartate/other aminotransferase (Asp_trans)
Type: Family

Aspartate aminotransferase is important for the metabolism of amino acids and Krebs-cycle related organic acids. In plants, it is involved in nitrogen metabolism and in aspects of carbon and energy metabolism. The enzyme catalyses the reaction:
L-aspartate + 2-oxoglutarate = oxaloacetate + L-glutamate
Aminotransferases share certain mechanistic features with other pyridoxal-phosphate-dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue . This family also includes some aromatic-amino-acid aminotransferases such as L-tyrosine:2-oxoglutarate aminotransferase ucdG and Tyrosine aminotransferase TyrAT .
Bunyavirus non-structural protein NS-s (Bunya_NSs)
Type: Family

The NSS proteins are encoded in the S RNA from ssRNA negative-strand viruses . The S RNA also codes for the nucleoprotein N. The two main products are read from overlapping reading frames in the viral complementary sequence.
Ezrin/radixin/moesin-like (Ez/rad/moesin-like)
Type: Family

This entry represents the ERM family consisting of three closely related proteins, ezrin, radixin, and moesin, that work as cross-linkers between plasma membranes and actin-based cytoskeletons as well as taking part in signal transduction.

The ERM family consists of three closely-related proteins, ezrin, radixin and moesin . Ezrin was first identified as a constituent of microvilli , radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions , and moesin as a heparin binding protein , which is particularly important in immunity acting on both T and B-cells homeostasis and self-tolerance . Members of this family have been associated with axon-associated Schwann cell (SC) motility and the maintenance of the polarity of these cells . A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein) . ERM molecules contain 3 domains, an N-terminal globular domain, an extended α-helical domain and a charged C-terminal domain . Ezrin, radixin and merlin also contain a polyproline region between the helical and C-terminal domains. The N-terminal domain is highly conserved, and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain . ERM proteins crosslink actin filaments with plasma membranes. They co-localise with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains . The α-helical region is involved in intramolecular masking of protein-protein interaction sites which regulates the activity of this proteins .
Steroidogenic acute regulatory protein-like (StAR-like)
Type: Family

This entry represents subsets of the steroidogenic acute regulatory (StAR) proteins from animals. Proteins in this family contain a START domain, which binds lipids, including sterols .
Notch domain (Notch_dom)
Type: Domain

The Notch domain is also called the 'DSL' domain or the Lin-12/Notch repeat (LNR). The LNR region is present only in Notch related proteins C-terminal to EGF repeats. The lin-12/Notch proteins act as transmembrane receptors for intercellular signals that specify cell fates during animal development. In response to a ligand, proteolytic cleavages release the intracellular domain of Notch, which then gains access to the nucleus and acts as a transcriptional co-activator . The LNR region is supposed to negatively regulate the Lin-12/Notch proteins activity. It is a triplication of an around 35-40 amino acids module present on the extracellular part of the protein . Each module contains six cysteine residues engaged in three disulphide bonds and three conserved aspartate and asparagine residues . The biochemical characterisation of a recombinantly expressed LIN-12.1 module from the human Notch1 receptor indicate that the disulphide bonds are formed between the first and fifth, second and fourth, and third and sixth cysteines. The formation of this particular disulphide isomer is favored by the presence of Ca
2+
, which is also required to maintain the structural integrity of the rLIN-12.1 module. The conserved aspartate and asparagine residues are likely to be important for Ca
2+
binding, and thereby contribute to the native fold.
Esterase-like (Esterase-like)
Type: Family

This family contains several seemingly unrelated proteins, including human esterase D

; mycobacterial antigen 85 , which is responsible for the high affinity of mycobacteria to fibronectin; Corynebacterium glutamicum major secreted protein PS1; and a number of proteins from Escherichia coli, yeast, mycobacteria and Haemophilus influenzae. Proteins in this entry share the typical AB hydrolase fold including esterases with broad specificity. Among them, S-formylglutathione hydrolases, such as YeiG and FrmB from bacteria

; the three related serine hydrolases Iron(III) enterobactin esterase fes (

), Iron(III) salmochelin esterase iroD (

) and iroE (

) from E. coli which are esterases for the apo and Fe3-bound forms of enterobactin iroB .
Arsenical pump membrane protein, ArsB (Arsenical_pump_ArsB)
Type: Family

Arsenic is a toxic metalloid whose trivalent and pentavalent ions inhibit a variety of biochemical processes. Operons that encode arsenic resistance have been found in multicopy plasmids from both Gram-positive and Gram-negative bacteria . The resistance mechanism is encoded from a single operon, which houses an anion pump. The pump has two polypeptide components: a catalytic subunit (the ArsA protein), which functions as an oxyanion-stimulated ATPase; and an arsenite export component (the ArsB protein), which is associated with the inner membrane . The ArsA and ArsB proteins are thought to form a membrane complex that functions as an anion-translocating ATPase.

The ArsB protein is distinguished by its overall hydrophobic character, in keeping with its role as a membrane-associated channel. Sequence analysis reveals the presence of 13 putative transmembrane (TM) regions.
Clathrin adaptor complex, small chain (Clathrin_sm-chain_CS)
Type: Conserved_site

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. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer .

This entry represents the small sigma subunit of various adaptins from different AP clathrin adaptor complexes (including AP1, AP2, AP3 and AP4), and the zeta subunit of various coatomer (COP) adaptors. The small sigma subunit of AP proteins have been characterised in several species . The sigma subunit plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The zeta subunit of coatomers (zeta-COP) is required for coatomer binding to Golgi membranes and for coat-vesicle assembly .
Glycoside hydrolase family 26 (Glyco_hydro_26)
Type: Family

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 26

encompasses mainly mannan endo-1,4-beta-mannosidases (

) and also beta-1,3-xylanases. Mannan endo-1,4-beta-mannosidase hydrolyses mannan and galactomannan, but displays little activity towards other plant cell wall polysaccharides . The enzyme randomly hydrolyses 1,4-beta-D-linkages in mannans, galacto-mannans, glucomannans and galactoglucomannans.
Imidazoleglycerol-phosphate dehydratase (ImidazoleglycerolP_deHydtase)
Type: Family

Imidazoleglycerol-phosphate dehydratase (IGPD;

) catalyzes the dehydration of imidazole glycerol phosphate to imidazole acetol phosphate, the sixth step of histidine biosynthesis in plants and microorganisms where the histidine is synthesized de novo. There is an internal repeat in the protein domain that is related by pseudo-dyad symmetry, perhaps as a result of an ancient gene duplication. The apo-form of IGPD exists as a catalytically inactive trimer which, in the presence of specific divalent metal cations such as manganese (Mn2+), cobalt (Co2+), cadmium (Cd2+), nickel (Ni2+), iron (Fe2+) and zinc (Zn2+), assembles to form a biologically active high molecular weight metalloenzyme; a 24-mer with 4-3-2 symmetry. Each 24-mer has 24 active sites, and contains around 1.5 metal ions per monomer, each monomer contributing residues to three separate active sites.

IGPD enzymes are monofunctional in fungi, plants, archaea and some eubacteria while they are encoded as bifunctional enzymes in other eubacteria, such that the enzyme is fused to histidinol-phosphate phosphatase, the penultimate enzyme of the histidine biosynthesis pathway. The histidine biosynthesis pathway is a potential target for development of herbicides, and IGPD is a target for the triazole phosphonate herbicides .
Iron-sulfur cluster carrier protein-like, conserved site (Mrp-like_CS)
Type: Conserved_site

This entry represents a conserved region found in Iron-sulfur cluster carrier protein from Escherichia coli protein (Mrp), a 41kDa ATP-binding protein of unknown function, and other Fe-S cluster protein sequences spread among all cellular organisms. Homologues are present in other bacteria including Bacillus subtilis ybaL, Haemophilus influenzae HI1277, Synechocystis sp. (strain PCC 6803) slr0067; and also in eukaryotes, for example human NBP, yeast NBP35 and YIL003w, Caenorhabditis elegans F10G8.6; and in archaebacteria, for example Methanocaldococcus jannaschii (Methanococcus jannaschii) MJ0283.
Cannabinoid receptor type 1 (Canbinoid_rcpt_1)
Type: Family

Cannabinoid receptors are a class of cell membrane receptors that belong to the rhodopsin-like G-protein coupled receptor (GPCR) family . Typical of G protein-coupled receptors, cannabinoid receptors contain seven transmembrane spanning domains . Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, such as N-arachidonoylethanolamine and 2-arachidonoyl glycerol (produced by the mammalian body), plant cannabinoids, such as tetrahydrocannabinol (produced by the plant
Cannabis sativa
) and synthetic cannabinoids, such as HU-210 . Currently, two known cannabinoid receptor subtypes have been identified, CB1 receptor and CB2 receptor , and are phylogenetically restricted to the chordate branch of the animal kingdom . The International Union of Basic and Clinical Pharmacology (IUPHAR) has identified five pharmacological targets that could be used to find new cannabinoid receptors or channels , which has resulted in a number of cannabinoid receptors being considered. TRP vanilloid 1, which is thought to function as an ionotropic cannabinoid receptor , and some deorphanised GPCRs : GPR18, GPR55, GPR119. However, according to the criteria, no channel, non-CB1/CB2 established receptor or deorphanised receptor can currently be classified fully as a novel cannabinoid receptor .

This entry represents cannabinoid receptor 1 (CB1), which is found mainly in the central nervous system and is largely responsible for mediating the effects of cannabinoid binding in the brain, with high levels occurring in the basal ganglia, hippocampus, cerebellum, cerebral cortex, with more moderate levels in the hypothalamus . The CB1 receptor is also present in some non-neuronal cells and tissues, for example leukocytes and testis . The CB1 receptor is activated by cannabinoids, generated naturally inside the body by endocannabinoids neurotransmitters, such as anandamide and 2-arachidonoyl glyceride (2-AG) ; or introduced into the body by plant cannabinoids, such as the compound tetrahydrocannabinol THC , an active ingredient of the psychoactive drug cannabis or a related synthetic compound. The CB1 receptor has been extensively characterised for a range of biological responses . Nervous system responses to THC and other cannabinoid receptor agonists include therapeutically beneficial effects of analgesia , attenuation of the nausea and vomiting in cancer chemotherapy , appetite stimulation in wasting syndromes and decreased intestinal motility . Untoward side effects accompanying these therapeutic responses include alterations in cognition and memory , dysphoria/euphoria and sedation . It is generally accepted that the CB1 receptor functions to mediate inhibition of on-going release of certain excitatory and inhibitory neurotransmitters .
Glycosyl transferase, family 35 (Glyco_trans_35)
Type: Family

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'.

Glycosyltransferase family 35

comprises enzymes with only one known activity; glycogen and starch phosphorylase (

).
Transcription factor TFIIB (TFIIB)
Type: Family

In eukaryotes, transcription initiation by polymerase II is modulated by both general and specific transcription factors. The general factors (which include TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIG and TFIIH) operate through common promoter elements, such as the TATA box. Transcription factor IIB (TFIIB) is of central importance in transcription of class II genes. It associates with TFIID-TFIIA bound to DNA (the DA complex) to form a ternary TFIID-IIA-IBB (DAB) complex, which is recognised by RNA polymerase II . TFIIB comprises ~315-340 residues and contains an imperfect C-terminal repeat of a 75-residue domain that may contribute to the symmetry of the folded protein.

Proteins in this entry also include transcription factor IIIB subunit Brf1, which shares protein sequence similarity with TFIIB. In budding yeast, Brf1 interacts with several initiation-specific subunits of the pol III machinery, TBP, beta", TFC4p and the pol III subunits C34 and C17 .
7Fe ferredoxin (7Fe_ferredoxin)
Type: Family

Ferredoxins are iron-sulphur proteins that mediate electron transfer in a range of metabolic reactions. The proteins fall into several subgroups according to the nature of their iron-sulphur cluster(s). The 7Fe ferredoxins contain both 4Fe-4S and 3Fe-4S centres. The 4Fe-4S domain is similar to those found in other bacterial-type ferredoxins. The 3D structure of the 7Fe ferredoxin from Azotobacter vinelandii has been determined to 1.9 A resolution . The fold belongs to the α + β class, with 3 helices and 4 strands forming a barrel-like structure, and an extruded loop containing 3 of the 4 cysteinyl residues of the iron-sulphur cluster.
TATA-box binding protein (TBP)
Type: Family

The TATA-box binding protein (TBP) is required for the initiation of transcription by RNA polymerases I, II and III, from promoters with or without a TATA box . TBP associates with a host of factors, including the general transcription factors SL1, TFIIA, -B, -D, -E, and -H, to form huge multi-subunit pre-initiation complexes on the core promoter. Through its association with different transcription factors, TBP can initiate transcription from different RNA polymerases. There are several related TBPs, including TBP-like (TBPL) proteins . TBP binds directly to the TATA box promoter element, where it nucleates polymerase assembly, thus defining the transcription start site.

The C-terminal core of TBP (~180 residues) is highly conserved and contains two 77-amino acid repeats that produce a saddle-shaped structure that straddles the DNA; this region binds to the TATA box and interacts with transcription factors and regulatory proteins . By contrast, the N-terminal region varies in both length and sequence.
Peptidase C15, pyroglutamyl peptidase I (Peptidase_C15)
Type: Family

This group of cysteine peptidases belong to MEROPS peptidase family C15 (pyroglutamyl peptidase I, clan CF). The type example being pyroglutamyl peptidase I of Bacillus amyloliquefaciens. There are similarities in structure between members of clan CF and members of three clans of metallopeptidases (MC, MF and MH) and all four are included in the same superfamily (phosphorylase/hydrolase-like fold) by the SCOP database. Members of clan CF have an α/β/α sandwich fold .

Pyroglutamyl peptidase I (also known as pyrrolidone carboxyl peptidase, Pcp or PYRase) is an exopeptidase that hydrolytically removes the pGlu from pGlu-peptides or pGlu-proteins . PYRase has been found in prokaryotes and eukaryotes where at least two different classes have been characterised: the first containing bacterial and animal type I PYRases, and the second containing animal type II and serum PYRases. Type I and bacterial PYRases are soluble enzymes, while type II PYRases are membrane-bound. The primary application of PYRase has been its utilisation for protein or peptide sequencing, and bacterial diagnosis . The conserved residues Cys-144 and His-168 have been identified by inhibition and mutagenesis studies .
Prion protein (Prion)
Type: Family

Prion protein (PrP-c) is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) .

The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process.
TEA/ATTS domain (TEA/ATTS_dom)
Type: Domain

The TEA domain is a DNA-binding region of about 66 to 68 amino acids that has been named after the two proteins that originally defined the domain: TEF-1 and AbaA. The TEA domain is located toward the N terminus of eukaryotic transcription factors of the TEA/ATTS family. It shows a three-helix bundle with a homeodomain fold . Two α-helices are nearly anti-parallel and pack on either side of the third one, which is the DNA-recognition helix of the TEA domain. Phosphorylation of one or both of the two conserved serines found on the DNA-binding surface could interfere with DNA-binding activity, by introducing electrostatic repulsion and/or steric hindrance, and help regulate the transcription factor activity of the proteins .
Peptidase M17, leucyl aminopeptidase, C-terminal (Peptidase_M17_C)
Type: Domain

This domain is found in a group of metallopeptidases that belong to the MEROPS peptidase family M17 (leucyl aminopeptidase family, clan MF), including leucyl aminopeptidase from Bos taurus (Bovine).

Aminopeptidases are exopeptidases involved in the processing and regular
turnover of intracellular proteins, although their precise role in cellular
metabolism is unclear . Leucine aminopeptidases cleave leucine residues
from the N-terminal of polypeptide chains, but substantial rates are evident
for all amino acids .

The enzymes exist as homo-hexamers, comprising 2 trimers stacked on top of
one another . Each monomer binds 2 zinc ions and folds into 2 α/β-type quasi-spherical globular domains, producing a comma-like shape . The N-terminal 150 residues form a 5-stranded β-sheet with 4 parallel and 1 anti-parallel strand sandwiched between 4 α-helices . An α-helix extends into the C-terminal domain, which comprises a central 8-stranded saddle-shaped β-sheet sandwiched between groups of helices, forming the monomer hydrophobic core . A 3-stranded β-sheet resides on the surface of the monomer, where it interacts with other members of the hexamer . The 2 zinc ions and the active site are entirely located in the C-terminal catalytic domain .

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
Proto-oncogene Mas (Proto-oncogene_Mas)
Type: Family

The mas proto-oncogene was intially discovered following co-transfection with DNA isolated from a human epidermal carcinoma. It efficiently induces tumorigenicity and has weak focus-inducing activity in NIH 3T3 cells. To date, it is the only oncogene to have been sequenced that encodes a 7TM protein. The oncogene is a GPCR which binds the angiotensin-II metabolite angiotensin (1-7) . It is therefore thought that MAS1 receptor agonists have similar therapeutic effects as angiotensin-II receptor antagonists including lowering blood pressure . In the CNS, high levels of the mas proto-oncogene transcript are present in the cerebral cortex, with lower amounts in the hippocampus and cerebellum. In the periphery, it is expressed in low levels in the kidney, adrenals and liver. The rat RTA protein has some similarity to the mas proto-oncogene sequence.