SII-SWORD/CoKE huggingface dataset:
TSC22/Bun (TSC22/Bun)
Type: Family

This entry includes a group of eukaryotic proteins that are evolutionary related and involved in transcriptional regulation. These proteins are highly similar in a region of about 50 residues that include a conserved leucine-zipper domain most probably involved in homo- or hetero-dimerisation. Proteins included in this entry are:

Vertebrate proteins TSC22 1-4 , transcriptional regulators that act in different pathways, for instance, TSC22-1 acts on C-type natriuretic peptide (CNP) promoter , it also promotes CASP3-mediated apoptosis and positively regulates TGF-beta signaling ; TSC22-3 (also known as DIP) protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11 and it also contributes to enhancement of TGF-beta signaling by binding to and modulating the transcription activator activity of SMAD4 .

Drosophila protein bunched (gene bun) (also known as shortsighted), a probable transcription factor required for peripheral nervous system morphogenesis, eye development and oogenesis.

Caenorhabditis elegans protein tsct-1 (also known as T18D3.7), whose function is unknown.
Dihydroxy-acid/6-phosphogluconate dehydratase, N-terminal (ILV_EDD_N)
Type: Domain

This is the N-terminal domain of Ilv/ED dehydratase protein family which includes dihydroxy-acid/6-phosphogluconate dehydratases, and pentonate dehydratases . This domain is composed of a β-sheet with four parallel β-strands surrounded by four α-helices and forms a binding site for a [2Fe-2S] cluster and a Mg2+ ion .

Members of this entry are involved in various biosynthetic and carbohydrate metabolic pathways . Dihydroxy-acid dehydratase catalyses the fourth step in the biosynthesis of isoleucine and valine, the dehydration of 2,3-dihydroxy-isovaleic acid into alpha-ketoisovaleric acid. 6-Phosphogluconate dehydratase catalyses the first step in the Entner-Doudoroff pathway, the dehydration of 6-phospho-D-gluconate into 6-phospho-2-dehydro-3-deoxy-D-gluconate. They consist of two domains, N- and C-terminal, the latter contains residues (Ser490 and Thr492) that participate in the formation of the substrate binding site.
Acyl-CoA-binding protein, ACBP (Acyl-CoA-binding_protein)
Type: Domain

Acyl-CoA-binding protein (ACBP) is a small (10 Kd) protein that binds medium-and long-chain acyl-CoA esters with very high affinity and may function as an intracellular carrier of acyl-CoA esters . ACBP is also known as diazepam binding inhibitor (DBI) or endozepine (EP) because of its ability to displace diazepam from the benzodiazepine (BZD) recognition site located on the GABA type A receptor. It is therefore possible that this protein also acts as a neuropeptide to modulate the action of the GABA receptor .

ACBP is a highly conserved protein of about 90 residues that is found in all four eukaryotic kingdoms, Animalia, Plantae, Fungi and Protista, and in some eubacterial species .

Although ACBP occurs as a completely independent protein, intact ACB domains have been identified in a number of large, multifunctional proteins in a variety of eukaryotic species. These include large membrane-associated proteins with N-terminal ACB domains, multifunctional enzymes with both ACB and peroxisomal enoyl-CoA Delta(3), Delta(2)-enoyl-CoA isomerase domains, and proteins with both an ACB domain and ankyrin repeats (

) .

The ACB domain consists of four α-helices arranged in a bowl shape with a highly exposed acyl-CoA-binding site. The ligand is bound through specific interactions with residues on the protein, most notably several conserved positive charges that interact with the phosphate group on the adenosine-3'phosphate moiety, and the acyl chain is sandwiched between the hydrophobic surfaces of CoA and the protein .

Other proteins containing an ACB domain include:

Endozepine-like peptide (ELP) (gene DBIL5) from mouse . ELP is a testis-specific ACBP homologue that may be involved in the energy metabolism of the mature sperm.

MA-DBI, a transmembrane protein of unknown function which has been found in mammals. MA-DBI contains a N-terminal ACB domain.

DRS-1 , a human protein of unknown function that contains a N-terminal ACB domain and a C-terminal enoyl-CoA isomerase/hydratase domain.
Voltage-dependent calcium channel, L-type, beta subunit (VDCC_L_bsu)
Type: Family

This entry represents the beta subunits found in L-type voltage-gated calcium channels.

Co-expression of beta subunit mRNA with alpha-1 subunit mRNA in xenopus oocytes produces increased calcium currents, which are accompanied by a shift in the voltage-dependence of activation to more negative membrane potentials. Conversely, microinjection of antisense oligonucleotides to beta subunit mRNA produces decreased calcium currents and shifts voltage-dependent activation to more positive membrane potentials. There are four distinct beta subunits: beta-1, beta-2, beta-3 and beta-4; and the magnitude of the shift in the voltage-dependence of activation of change to membrane potentials varies with the particular subtype .

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.
Hemopexin-like domain (Hemopexin-like_dom)
Type: Domain

Hemopexin (

) is a serum glycoprotein that binds haem and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation . Hemopexin prevents haem-mediated oxidative stress. Structurally hemopexin consists of two similar halves of approximately two hundred amino acid residues connected by a histidine-rich hinge region. Each half is itself formed by the repetition of a basic unit of some 35 to 45 residues. Hemopexin-like domains have been found in two other types of proteins, vitronectin , a cell adhesion and spreading factor found in plasma and tissues, and matrixins MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-15 and MMP-16, members of the matrix metalloproteinase family that cleave extracellular matrix constituents . These zinc endopeptidases, which belong to MEROPS peptidase subfamily M10A, have a single hemopexin-like domain in their C-terminal section. It is suggested that the hemopexin domain facilitates binding to a variety of molecules and proteins, for example the HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).
Somatostatin receptor family (Somatstn_rcpt)
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 the somatostatin family.
Creatinase, N-terminal (Creatinase_N)
Type: Domain

Creatinase or creatine amidinohydrolase (

) catalyses the conversion of creatine and water to sarcosine and urea. The enzyme works as a homodimer, and is induced by choline chloride. Each monomer of creatinase has two clearly defined domains, a small N-terminal domain, and a large C-terminal domain.

The structure of the C-terminal region represents 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 .

This entry represents the N-terminal domain of creatinase, aminopeptidase P, prolidases and similar proteins.
Small ribosomal subunit protein uS15 (Ribosomal_uS15)
Type: Family

Small ribosomal subunit protein uS15 is one of the proteins from the small ribosomal subunit. In Escherichia coli, this protein binds to 16S ribosomal RNA and functions at early steps in ribosome assembly. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacterial and plant chloroplast S15; archaeal Haloarcula marismortui HmaS15 (HS11); yeast mitochondrial S28; and mammalian, yeast, Brugia pahangi and Wuchereria bancrofti S13. S15 is a protein of 80 to 250 amino-acid residues.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Hydroxymethylglutaryl-coenzyme A synthase, active site (HMG_CoA_synt_AS)
Type: Active_site

Hydroxymethylglutaryl-CoA synthase (

) catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to produce HMG-CoA and CoA, the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA .

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria . In vertebrates, there are two isozymes located in different subcellular compartments: a cytosolic form that is the starting point of the mevalonate pathway (leads to cholesterol and other sterolic and isoprenoid compounds), and a mitochondrial form responsible for ketone body biosynthesis. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi . In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes .

This entry represents the sequence surrounding the catalytic cysteine required for nucleophilic attack in the first step of the reaction, the acetylation of the enzyme by acetyl-CoA.
DEP domain (DEP_dom)
Type: Domain

This entry represents the DEP (Dishevelled, Egl-10 and Pleckstrin) domain, a globular domain of about 80 residues that is found in over 50 proteins involved in G-protein signalling pathways. It was named after the three proteins it was initially found in:

Dishevelled (Dsh and Dvl), which play a key role in the transduction of the Wg/Wnt signal from the cell surface to the nucleus; it is a segment polarity protein required to establish coherent arrays of polarized cells and segments in embryos, and plays a role in wingless signalling.

Egl-10, which regulates G-protein signalling in the central nervous system.

Pleckstrin, the major substrate of protein kinase C in platelets; Pleckstrin contains two PH domains flanking the DEP domain.

Mammalian regulators of G-protein signalling also contain these domains, and regulate signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving them into their inactive GDP-bound form. It has been proposed that the DEP domain could play a selective role in targeting DEP domain-containing proteins to specific subcellular membranous sites, perhaps even to specific G protein-coupled signaling pathways . Nuclear magnetic resonance spectroscopy has revealed that the DEP domain comprises a three-helix bundle, a β-hairpin 'arm' composed of two β-strands and two short β-strands in the C-terminal region .
Small ribosomal subunit protein eS27 (Ribosomal_eS27)
Type: Family

S27 is involved in rRNa processing, direct binding to mRNA and degradation of damaged mRNAs. S27 is a C4 zinc finger protein of the CX2CX14-16CX2C class. Zinc finger motifs in ribosomal proteins mediate protein-RNA interactions, however it has been suggested the zinc finger in S27 possibly has no functional importance for modern S27 proteins, and is rather a fossil from ancient evolution. This view is supported by the sequence alignment, showing that the zinc finger motif is not strictly conserved . A number of eukaryotic and archaeal ribosomal proteins can be grouped on the basis of sequence similarities. One of these families include mammalian, yeast, Chlamydomonas reinhardtii and Entamoeba histolytica S27, and Methanocaldococcus jannaschii (Methanococcus jannaschii) MJ0250 .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
RasGAP protein, C-terminal (RasGAP_C)
Type: Domain

This domain can be found in the C terminus of the IQGAP family members, including human IQGAP1/2/3, S. cerevisiae Iqg1 and S. pombe Rng2. Some members function in cytoskeletal remodelling . Human IQGAP1 is a scaffolding protein that can assemble multi-protein complexes involved in cell-cell interaction, cell adherence, and movement via actin/tubulin-based cytoskeletal reorganization . IQGAP1 is also a regulator of the MAPK and Wnt/beta-catenin signaling pathways . Iqg1 and Rng2 are required for actomyosin ring construction during cytokinesis .
THIF-type NAD/FAD binding fold (ThiF_NAD_FAD-bd)
Type: Domain

This domain is a NAD/FAD-binding fold found in ubiquitin activating E1 family and members of the bacterial ThiF/MoeB/HesA family. It is repeated in Ubiquitin-activating enzyme E1 .

ThiF/MoeB/HesA are involved in molybdopterin and thiamine biosynthesis. The common reaction mechanism catalysed by MoeB and ThiF, like other E1 enzymes, begins with a nucleophilic attack of the C-terminal carboxylate of MoaD and ThiS, respectively, on the alpha-phosphate of an ATP molecule bound at the active site of the activating enzymes, leading to the formation of a high-energy acyladenylate intermediate and subsequently to the formation of a thiocarboxylate at the C termini of MoaD and ThiS. MoeB, as the MPT synthase (MoaE/MoaD complex) sulfurase, is involved in the biosynthesis of the molybdenum cofactor, a derivative of the tricyclic pterin, molybdopterin (MPT) . ThiF catalyses the adenylation of ThiS, as part of the biosynthesis pathway of thiamin pyrophosphate (vitamin B1) .

The post-translational attachment of ubiquitin (

) to proteins (ubiquitinylation) alters the function, location or trafficking of a protein, or targets it to the 26S proteasome for degradation . Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2,

), and a ubiquitin ligase (E3,

,

), which work sequentially in a cascade . The E1 enzyme is responsible for activating ubiquitin, the first step in ubiquitinylation. The E1 enzyme hydrolyses ATP and adenylates the C-terminal glycine residue of ubiquitin, and then links this residue to the active site cysteine of E1, yielding a ubiquitin-thioester and free AMP. To be fully active, E1 must non-covalently bind to and adenylate a second ubiquitin molecule. The E1 enzyme can then transfer the thioester-linked ubiquitin molecule to a cysteine residue on the ubiquitin-conjugating enzyme, E2, in an ATP-dependent reaction.
Cyclic nucleotide-binding domain (cNMP-bd_dom)
Type: Domain

Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues . The best studied of these proteins is the prokaryotic catabolite gene activator (also
known as the cAMP receptor protein) (gene crp) where such a domain is known to be composed of three α-helices and a distinctive eight-stranded, antiparallel β-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the β-barrel. cAMP- and cGMP-dependent protein kinases (cAPK and cGPK) contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chain and a regulatory chain, which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterised, one is found in rod cells where it plays a role in visual signal transduction.