SII-SWORD/CoKE huggingface dataset:
Transcription factor DP (Transcrpt_fac_DP)
Type: Family

The DP proteins function as binding partners for E2F transcription factors. The association of DP with E2F can either enhances or repress E2F-dependent transcriptional activity.

The activities of both DP and E2F proteins are under cell cycle control, being influenced by the level of phosphorylation imparted through the cell cycle regulated activity of cyclin-dependent kinases. Molecules that function to positively regulate the G1/S transition, such as cyclin-cdk complexes, and negatively regulate it, such as the cdk inhibitors, converge on the Rb pathway. A principal role of pRb is in the regulation of the E2F/DP transcription factors, activity of which determines cell-cycle progression .

Both DP and E2F proteins are endowed with proto-oncogenic activity and, conversely, have been implicated in regulating apoptosis .

The DP proteins have been widely evolutionarily conserved and can be found in organisms ranging from Arabidopsis thaliana (Mouse-ear cress) to Homo sapiens (Human).
Schwannomin interacting protein 1, C-terminal (SCHIP_1_C)
Type: Domain

This entry represents the C-terminal domain of mammalian SCHIP-1. This domain contains a leucine zipper coiled-coil structure implicated in their dimerization . This domain is also found in its isoforms such as IQCJ-SCHIP-1 (IQ motif containing J-Schwannomin-Interacting Protein 1). The N-terminal part of IQCJ-SCHIP-1 possesses an additional IQ motif, which typically serves as a Ca2+-independent CaM-binding site .

SCHIP-1 is a coiled-coil protein that specifically associates with schwannomin in vitro and in vivo. The product of the neurofibromatosis type 2 (NF2) tumour suppressor gene, known as schwannomin or merlin, is involved in NF2-associated and sporadic schwannomas and meningiomas. It is closely related to the ezrin-radixin-moesin family members, which link membrane proteins to the cytoskeleton. Association with SCHIP-1 can be observed only with some naturally occurring mutants of schwannomin, or a schwannomin spliced isoform lacking exons 2 and 3, but not with the schwannomin isoform exhibiting growth-suppressive activity .
Mandelate racemase (Mandelate_racemase)
Type: Family

Mandelate racemase (

) (MR) in certain bacteria, including Pseudomonas putida, utilise D or L mandelic acid as sole carbon source for energy. Mandelate racemase and muconate lactonizing enzyme (

) (MLE) are two bacterial enzymes involved in aromatic acid catabolism. They catalyze mechanistically distinct reactions yet they are related at the level of their primary, quaternary (homooctamer) and tertiary structures . A crystal structure has been described .
Protein phosphatase 2C (PP2C)
Type: Family

Protein phosphatase 2C (PP2C) is one of the four major classes of mammalian serine/threonine specific protein phosphatases (

). PP2C is a monomeric enzyme of about 42kDa, that shows broad substrate specificity and is dependent on divalent cations (mainly manganese and magnesium) for its activity. The exact physiological role is still unclear. Three isozymes are currently known in mammals: PP2C-alpha, -beta and -gamma. In yeast, there are at least four PP2C homologues: phosphatase PTC1
that have weak tyrosine phosphatase activity in addition to its activity on serines, phosphatases PTC2 and PTC3, and hypothetical protein YBR125c. Isozymes of PP2C are also known from Arabidopsis thaliana (Mouse-ear cress) (ABI1, PPH1),
Caenorhabditis elegans (FEM-2, F42G9.1, T23F11.1), Leishmania chagasi and
Paramecium tetraurelia. In A. thaliana, the kinase associated protein phosphatase (KAPP)
is an enzyme that dephosphorylates the Ser/Thr receptor-like kinase RLK5 and contains a C-terminal PP2C domain. This family also includes a broad spectrum phosphatase PP1M and Fem-2 which dephosphorylates auto-phosphorylated Ca2+/calmodulin-dependent protein kinase unc-43/CAMKII .

PP2C does not seem to be evolutionary related to the main family of serine/ threonine phosphatases: PP1, PP2A and PP2B. However, it is significantly similar to the catalytic subunit of pyruvate dehydrogenase phosphatase
(

) (PDPC) , which catalyses dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex. PDPC is a mitochondrial enzyme and, like PP2C, is magnesium-dependent.
Aminobutyraldehyde dehydrogenase (Aminobutyraldehyde_DH)
Type: Family

Aminobutyraldehyde dehydrogenase functions in the putrescine degradation pathway. It catalyses the oxidation of 4 aminobutyraldehyde to 4 aminobutyrate, a neurotransmitter. YdcW encodes gamma-aminobutyraldehyde dehydrogenase (ABALDH) in the wild-type Escherichia coli (strain K12). It is a tetramer and when coupled with YgjG putrescine transaminase in vitro, putrescine was converted into gamma-aminobutyric acid . The tetramer is composed of identical subunits. YdcW can also oxidize N-alkyl medium-chain aldehydes, but with a lower catalytic efficiency . The same enzyme from Arthrobacter sp. utilises both NAD+ and NADP+ as coenzymes. It functions optimally at pH 8.0 .
Proline oxidase family (Proline_oxidase)
Type: Family

This entry includes a group of proline dehydrogenases (proline oxidases) found in bacteria, archaea and eukaryotes (mitochondria).
Achaete-scute transcription factor-related (MASH1/Ascl1a-like)
Type: Family

Basic helix-loop-helix proteins (bHLH) are a group of eukaryotic transcription factors that exert a determinative influence in a variety of developmental pathways. These transcription factors are characterised by a highly evolutionary conserved bHLH domain that mediates specific dimerisation . They facilitate the conversion of inactive monomers to trans-activating dimers at appropriate stages of development .

Proteins in this entry include MASH1/Ascl1a and related proteins from plants, worms, insects and mammals. MASH1/Ascl1a is a regulator of axonal growth across vertebrates and can induce modifications to the intrinsic state of neurons to promote functional regeneration in response to CNS injury .
Mitotic spindle checkpoint protein Bub1/Mad3 (Bub1/Mad3)
Type: Family

This represents the mitotic checkpoint serine/threonine-protein kinase Bub1.
Promotilin (Promotilin)
Type: Family

Promotilin can be cleaved into two chains: motilin and motilin-associated peptide. Motilin plays an important role in the regulation of interdigestive gastrointestinal motility and indirectly causes rhythmic contraction of duodenal and colonic smooth muscle .
P53-induced protein (P53_induced)
Type: Family

This entry includes p53-induced proteins that are members of the Pmp22 family of tetraspan membrane proteins.
Sarcoplasmic reticulum histidine-rich calcium-binding protein (HRC)
Type: Family

The histidine-rich calcium-binding protein of sarcoplasmic reticulum (HRC) may play a role in the regulation of calcium sequestration or release in the SR of skeletal and cardiac muscle . This protein is very acidic (31% of Asp and Glu) and rich in histidine (13%). The sequence of HRC contains 10 tandem repeats of a 26 to 29 amino acid residues domain. This domain starts with an invariant hexapeptide (HRHRGH), followed by a stretch of acidic residues. The end of the domain consists of an almost invariant nonapeptide (STESDRHQA). The highly acidic central cores of each repeat are likely to constitute the calcium-binding sites of HRC.
Telethonin (Telethonin)
Type: Family

Telethonin is found at the Z-disc of sarcomeres. It is the phosphorylation target of the kinase domain of titin, and is thought to play a role in muscle development . Deletion of the C terminus of titin, including the kinase domain, has been found to impair myofibrillogenesis . Mutations of telethonin cause limb-girdle muscular dystrophy type 2G .

Telethonin is a 167-residue protein which complexes with the large muscle protein, titin. The very N terminus of titin, composed of two immunoglobulin-like (Ig) domains, referred to as Z1 and Z2, interacts with the N-terminal region (residues 1-53) of telethonin, mediating the antiparallel assembly of two Z1Z2 domains. The C terminus of telethonin appears to induce dimerisation of this 2:1 titin/telethonin structure which thus forms a complex necessary for myofibril assembly and maintenance of the intact Z-disk of skeletal and cardiac muscles .
B Cell Lymphoma 9 (Bcl-9/Bcl-9l)
Type: Family

BCL9 is associated with B-cell acute lymphoblastic leukemia . This entry includes BCL9 and BCL9L. They are tissue-specific transcriptional cofactors that cooperate with beta-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind beta-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. They may also have a cytoplasmic role .
Endothelial protein C receptor (Endothetial_C_recpt)
Type: Family

Upon vascular injury, flowing blood is exposed to cells expressing tissue factor (TF) on their surfaces and FVII/FVIIa binds to its receptor/cofactor TF and is rapidly activated to FVIIa and the activity of bound FVIIa is dramatically enhanced. The TF/FVIIa complex activates zymogens factor X (FX) and factor IX (FIX). The FXa, in the absence of activated cofactor factor Va (FVa) generates only trace amounts of thrombin. Although insufficient to initiate fibrin polymerisation alone, these small amounts of thrombin, however, back activate factors V (FV), VIII (FVIII), and XI (FXI). FVIII and FV function as membrane-bound cofactors for proteinases FIXa and FXa, respectively increasing the Vmax of the reaction complexes dramatically. Amplification of the pro-coagulant response consequently occurs through formation of the tenase complex FIXa/FVIIIa and the thrombinase complex FXa/FVa that generate sufficient amounts of thrombin to mediate sustained haemostasis.

In addition to its function in cleaving soluble fibrinogen to form insoluble fibrin monomers, thrombin can also activate an anticoagulant pathway. Thrombomodulin (TM), a receptor present on the endothelial cell surface, binds thrombin and alters thrombin's substrate specificity through an allosteric mechanism. Bound to TM, thrombin can no longer efficiently proteolyse its pro-coagulant substrates FV, FVIII and fibrinogen. The thrombin-TM complex proteolytically activates its substrate protein C (PC) to activated protein C (APC). In complex with its cofactor protein S (PS), APC rapidly inactivates pro-coagulant factors FVa and FVIIIa by further proteolysis in a negative feedback loop. Activation of protein C by thrombin bound to thrombomodulin is enhanced by endothelial protein C receptor (EPCR). The EPCR is an N-glycosylated type I membrane protein and mutations in this EPCR gene have been associated with venous thromboembolism and myocardial infarction, as well as with late foetal loss during pregnancy.
GLTSCR protein, conserved domain (GSCR1_dom)
Type: Domain

This domain is found in glioma tumour suppressor candidate region gene 1 (GLTSCR1, also known as BICRAL) protein, and is typically between 105 and 124 amino acids in length. GLTSCR1 is a component of SWI/SNF chromatin remodeling subcomplex GBAF that carries out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner . There is a single completely conserved residue F that may be functionally important. Mutations in the gene for this protein in humans leads to the development of oligodendrogliomas . There is evidence that these protein interacts with SH3 domains .
The Golgi pH regulator/GPCR-type G protein (GPHR/GTG)
Type: Family

This entry include human Golgi pH regulators (GPHR) and GPCR-type G proteins (GTG1 and GTG2) from Arabidopsis.
Enamelin (Enamelin)
Type: Family

Enamelin is a secreted structural protein that acts to create dental enamel matrix. Enamelin protein is proteolytically cleaved into several products, which are identified by their molecular weights and appear to have different functions in different enamel compartments. It is not currently known how enamelin interacts with other proteins of the enamel matrix .

Enamelin mutations have been found to cause certain forms of amelogenesis imperfecta, a condition in which enamel is malformed .
Secretin precursor (Prosecretin)
Type: Family

A number of polypeptidic hormones, mainly expressed in the intestine or the pancreas, belong to a group of structurally related peptides . Members of the structurally similar group include glucagon, glicentin precursor, secretin, gastric inhibitory protein, vasoactive intestinal peptide (VIP), prealbumin, peptide HI-27 and growth hormone releasing factor.

Secretin is a 27-amino acid hormone produced by specific endocrine cells, S cells, located in the mucosa of the proximal small intestine . Secretin is initially synthesised as a precursor protein known as prosecretin . Secretin receptors are found in high levels in the pancreas, stomach and heart . They activate adenylyl cyclase through stimulation of G proteins . It is involved in a number of processes, among them, regulation of the pH of the duodenal content, food intake and water homeostasis . Secretin stimulates secretion of enzymes and ions in the pancreas and intestine, and is present in small amounts in the brain (e.g., in the hypothalamus, brainstem and cerebral cortex). Additionally, it plays a role in diet induced thermogenesis as it activates brown fat thermogenesis which stimulates lipolysis, a signal that is sensed in the brain and promotes satiation .
Tob1/2 (Tob1/2)
Type: Family

Tob1 and Tob2 are members of the BTG/Tob family.

The BTG/Tob family members contain an conserved N-terminal domain, known as APRO domain (AntiPROliferative) or BTG domain. In mammals, six family members have been identified: BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. They interact with CAF1, a subunit of the CCR4-NOT complex. They display antiproliferative properties as their ectopic expression in a variety of cell lines reduced cell proliferation .
Phospholipase D family (PLipase_D_fam)
Type: Family

Phospholipase D (PLD) catalyses the hydrolysis of the phosphodiester bond of glycerophospholipids to generate phosphatidic acid and a free head group. Phospholipase D activities have been detected in simple to complex organisms from viruses and bacteria to yeast, plants, and mammals . In higher organisms, PLD specifically catalyzes the hydrolysis of phosphatidylcholine (PC) to phosphatidic acid (PA) and choline and is activated in response to stimulators of vesicle transport, endocytosis, exocytosis, cell migration, and mitosis.

There are two mammalian phospholipase D genes whose products (PLD1 and PLD2) are alternatively spliced. Both forms have two highly conserved HKD motifs that are essential for catalysis and dimerisation . It has now been observed that there are abnormalities in PLD expression and activity in many human cancers .

Most bacteria use an enzyme belonging to the phospholipase D family as cardiolipin synthase. In contrast, eukaryotes and most actinobacteria use a cardiolipin synthase of the CDP-alcohol phosphatidyltransferase family .
Ionotropic glutamate receptor (Ionotropic_Glu_rcpt)
Type: Family

Ionotropic glutamate receptors (iGluRs) are a highly conserved family of ligand-gated ion channels present in animals, plants, and bacteria, which are best characterised for their roles in synaptic communication in vertebrate nervous systems . A variant subfamily of iGluRs, the Ionotropic Receptors (IRs), consist of non-glutamate-binding chemosensory receptors first identified in Drosophila melanogaster. They function in detecting odors and tastants .

The ionotropic glutamate receptor family mediates most forms of excitatory synaptic transmission in the mammalian CNS. These channels also are required for synaptic plasticity and learning. Glutamate receptors have been divided into AMPA, kainate, and NMDA subtypes based on differences in agonist response. NMDA receptors require both membrane depolarisation and glutamate-binding to open and are key regulators of long-term potentiation in the mammalian brain. AMPA and kainate receptors mediate fast synaptic transmission in the CNS. A fourth subfamily of glutamate receptors, delta, has recently been identified. The function of the delta family in neuronal signalling is unknown. Approximately 30 glutamate receptor genes are present in Drosophila, compared with 15 in Caenorhabditis elegans. Invertebrate glutamate receptors can be subdivided into kainate (15 genes in flies, four in worms), AMPA (three genes in both), NMDA (one type 1 and one type 2 gene in both species), and delta subfamilies (four genes in both) on the basis of sequence similarities with mammalian counterparts. In addition, several novel subtypes are present for which no mammalian homologues have been identified, though several show low similarity with the Arabidopsis Glur5 glutamate receptor. Mammalian NMDA receptors are tetramers containing two type 1 and two type 2 subunits. The genes found in worms and flies suggest conservation of this subunit structure in invertebrates. The Drosophila NMDA type 1 gene is expressed in brain. Genetic analysis in flies should reveal whether NMDA receptors have a universal role in cellular mechanisms of learning. Mutational analysis has been described for the Drosophila receptors GluR2A and GluR2B, which are involved in synaptic transmission at the larval neuromuscular junction.
Aquaporin 9 (Aquaporin_9)
Type: Family

Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol . In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures . The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.

Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel . The monomer has an overall "hourglass" structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.

Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water .

Aquaporin-9 was identified from human leukocytes by homology cloning . AQP9 has unusually broad solute permeability. It is expressed in hepatocyte plasma membranes and also in lung, small intestine and spleen cells . Expression of AQP9 in liver was induced up to 20-fold in rats fasted for 24 to 96 hours, and the AQP9 level gradually declined after re-feeding . AQP9 shares greater sequence identity with AQP3 and AQP7 than with other members of the family, suggesting that these 3 proteins belong to a subfamily.
Elongation Factor 3, ABC2 domain, chromodomain-like insertion (eEF3_ABC2_chromodomain-like)
Type: Domain

This entry includes members of the EF3 (Elongation Factor 3) family, which contain the ABC transporter domains and belong to the family of ABC (ATP-binding cassette) proteins. Yef3 (elongation factor 3A) and Hef3 (elongation factor 3B) are included in this entry.

The ribosomal elongation cycle requires two elongation factors: elongation factor 1 alpha (EF-1 alpha), which mediates the binding of an aminoacyl-tRNA to the ribosomal A site, and elongation factor 2 (EF-2), which catalyses the translocation reaction. In yeasts and other higher fungi, a third elongation factor, EF-3 is essential. EF-3 (also known as Yef3 in budding yeast) is required for the binding of the aminoacyl-tRNA-eEF1A-GTP ternary complex to the ribosomal A-site . EF-3 consists of an N-terminal HEAT repeat domain, followed by a four-helix bundle and two ABC-type ATPase domains, with a chromodomain inserted in ABC2 . The binding of EF-3 to ribosome may allow tRNA release . Hef3 is a weakly expressed functional homologue of YEF3.

This entry represents the chromodomain-like insertion in the ABC2 domain of eEF3, which is critical to eEF3 function .
DNA-directed RNA pol I, largest subunit, N-terminal domain (DNA-dir_RNA_pol1_lsu_N)
Type: Domain

This entry represents the N-terminal domain of the largest subunit of DNA-directed RNA polymerase I, also known as subunit RPA1, which constitutes the catalytic core component of RNA Pol I . The yeast member of this family is known as Rpb190 . This domain forms part of the active site.

DNA-dependent RNA polymerases (

) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-dependent RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

1. RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

2. RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

3. RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (greater than 100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.