SII-SWORD/CoKE huggingface dataset:
Eukaryotic porin/Tom40 (Porin_Euk/Tom40)
Type: Family

This entry represents both eukaryotic mitochondrial porins and Tom40 proteins.

Eukaryotic mitochondrial porins are voltage-dependent anion-selective channels (VDAC) that behave as general diffusion pores for small hydrophilic molecules . The channels adopt an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The eukaryotic mitochondrial porins are β-barrel proteins, composed of between 12 to 16 β-strands that span the mitochondrial outer membrane. Yeast contains two members of this family (genes POR1 and POR2); vertebrates have at least three members (genes VDAC1, VDAC2 and VDAC3) . They are related to the mitochondrial import receptor subunit Tom40 proteins, sharing a common evolutionary origin and structure .

Tom40 is a mitochondrion outer membrane protein and a component of the TOM (translocator of the outer mitochondrial membrane) complex, which is essential for import of protein precursors into mitochondria . In Saccharomyces cerevisiae, TOM complex is composed of the subunits Tom70, Tom40, Tom22, Tom20, Tom7, Tom6, and Tom5 . Tom40 is an integral membrane protein and the main structural component of the protein-conducting channel formed by the TOM complex . It is stabilised by other components, such as Tom5, Tom6, and Tom7 .
Small nuclear ribonucleoprotein Sm D2 (Sm_D2)
Type: Family

This entry represents the small nuclear ribonucleoprotein Sm D2 (Smd2) . Smd2 is a component of the SM core complex, a ring complex consists of six or seven subunits . SM complex associates with the snRNPs and is involved in the RNA-processing pathways .
DNA-directed DNA/RNA polymerase mu (DNA/RNApol_mu)
Type: Family

DNA-directed DNA/RNA polymerase mu is a gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ) . It participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination .
Phosphoglycerate kinase, euglenozoa (Pgk_euglenozoa)
Type: Family

Phosphoglycerate kinase (

) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to 3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.

Trypanosoma brucei and Crithidia fasciculata both contain three different phosphoglycerate kinase (PGK) genes, A, B and C . The genes B and C encode the major PGKs: the cytosolic and glycosomal PGKs, respectively. The PGK-A genes of both Trypanosomatid species encode open reading frames related to PGK, which have most active site residues conserved, but contain an insert of 80 amino acids at approximately position 80 of the 420 amino acids average PGK sequence . PGK-A may be a minor PGK with special function .

This entry includes phosphoglycerate kinase-A/B/C (PGK-A/B/C) from euglenozoa.
Diacylglycerol O-acyltransferase 1 (Diacylglycerol_acylTrfase1)
Type: Family

Diacylglycerol O-acyltransferase 1 (DGAT1) catalyses the final step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In plants, diacylglycerol O-acyltransferase 1 (DGAT1, TAG1) is a major enzyme for oil accumulation in seeds. It has complementary functions with PDAT1 acyltransferase that are essential for triacylglycerol synthesis and normal development of both seeds and pollen .

In mammals, DGAT1 is a multifunctional acyltransferase capable of synthesizing diacylglycerol, retinyl, and wax esters in addition to triacylglycerol . In liver, it plays a role in esterifying exogenous fatty acids to glycerol . It also functions as the major acyl-CoA retinol acyltransferase in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders .
Iodothyronine deiodinase I/III (Iodothyronine_deiodinase_I/III)
Type: Family

Iodothyronine deiodinase (

) (DI) is the vertebrate enzyme responsible for the deiodination of the prohormone thyroxine (T4 or 3,5,3',5'-tetraiodothyronine) into the biologically active hormone T3 (3,5,3'-triiodothyronine) and of T3 into the inactive metabolite T2 (3,3'-diiodothyronine). All known DI are proteins of about 250 residues that contain a selenocysteine at their active site. Three types of DI are known, type I is commonly found in the liver and kidney , type II is essential for providing the brain with the appropriate levels of T3 during the critical period of development, and type III (also known as thyroxine 5-deiodinase) is essential for the regulation of thyroid hormone inactivation during embryological development.

This entry represents type I and III Iodothyronine deiodinases.
Transcriptional enhancer factor TEF-5 (TEAD3) (TEF-5)
Type: Family

The TEAD family (also known as TEF family) transcription factors play a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumour suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. TEAD transcription factors act by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction .

Four TEAD genes exist in mammals (TEAD 1 to 4). TEAD3 (transcriptional enhancer factor TEF-5) has a role in placental development .
Transcriptional enhancer factor TEF-3 (TEAD4) (TEF-3)
Type: Family

The TEAD family (also known as the TEF family) transcription factors play a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. TEAD transcription factors act by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction .

Four TEAD genes exist in mammals (TEAD 1 to 4). TEAD4 protein (also known as TEF-3) was reported to regulate muscle-specific genes in cardiac and smooth muscle cells . Alternatively spliced transcripts for TEAD4 have been identified in human retinal vascular endothelial cells . TEAD4 protein has been shown to enhance VEGF gene expression in bovine aortic endothelial cells .
P-type ATPase, subfamily IB (P-typ_ATPase_IB)
Type: Family

P-ATPases (also known as E1-E2 ATPases) (

) are found in bacteria and in a number of eukaryotic plasma membranes and organelles . P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H
+
, Na
+
, K
+
, Mg
2+
, Ca
2+
, Ag
+
and Ag
2+
, Zn
2+
, Co
2+
, Pb
2+
, Ni
2+
, Cd
2+
, Cu
+
and Cu
2+
. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.

This entry represents the copper and cadmium-type heavy metal transporting P-type ATPases, and other related sequences that belong to the IB subfamily of P-type ATPases. Type IB ATPases are involved in transport of the soft Lewis acids: Cu
+
, Ag
+
, Cu
2+
, Zn
2+
, Cd
2+
, Pb
2+
and Co
2+
. These proteins are involved in a variety of processes in both prokaryotes and eukaryotes.
Mitogen-activated protein kinase kinase kinase 12 (MAPKKK12)
Type: Family

MAP3K12 (also known as leucine-zipper protein kinase (ZPK), dual leucine zipper-bearing kinase (DLK) or MAPK-upstream kinase (MUK)) is a MAPKKK class protein kinase that induces JNK/SAPK activation. MAP3K12 is known to interact with MUK-binding inhibitory protein (MBIP). MBIP contains two tandem leucine-zipper-like motifs; MBIP interacts with one of the two leucine-zipper-like motifs of MAP3K12 and inhibits the activity of MAP3K12 to induce JNK/SAPK activation . MAP3K12 is autophosphorylated on Ser/Thr in cytosol under basal conditions, and dephosphorylated when membrane-associated.
Mitogen-activated protein kinase kinase kinase 13 (MAPKKK13)
Type: Family

MAP3K13 (also known as leucine zipper-bearing kinase LZK) activates the c-Jun-NH2 terminal kinase (JNK) pathway through activation of the MAP kinase kinase MAP2K7 . MAP3K13 acts synergistically with peroxiredoxin-3 (PRDX3) to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B . MAP3K13 forms dimers/oligomers through its dual leucine zipper-like motif, and that this is necessary for activation of the JNK/SAPK pathway .
Predicted 3-demethylubiquinone-9 3-methyltransferase, bacterial (MTase_demethylubiq_bac)
Type: Family

This family represents a predicted bacterial type 3-demethylubiquinone-9 3-methyltransferase.
Hyaluronidase-3 (Hyaluronidase-3)
Type: Family

Hyaluronidases catalyse the random hydrolysis of (1->4)-linkages between N-acetyl-beta-D-glucosamine and D-glucuronate residues in hyaluronate (HA). Hyaluronidase-3 (HYAL3) lacked hyaluronidase activity when overexpressed in cultured cells, and may contribute to HA metabolism by augmenting the activity of HYAL1 .
Retinoic acid receptor responder protein 1 (TIG1)
Type: Family

Retinoic acid receptor responder protein 1 (RARRES1) is also known as TIG-1 (tazarotene-induced gene-1) as it is up-regulated by the synthetic retinoid tazarotene . TIG-1 is a tumor suppressor gene, its expression being frequently downregulated through promoter hypermethylation in various carcinomas . Inhibits the cytoplasmic carboxypeptidase AGBL2, and may regulate the alpha-tubulin tyrosination cycle .
Receptor tyrosine-protein phosphatase alpha (Tyr_Pase_rcpt_alpha)
Type: Family

This entry represents receptor tyrosine-protein phosphatase (PTP) alpha (

). PTP catalyses the dephosphorylation of protein tyrosine phosphate to protein tyrosine, and appear to play a pivotal role in insulin receptor signalling. It can exist as a single-pass membrane protein or in the cytoplasm. PTP-alpha is as a positive regulator of Src and Src family kinases, acting to dephosphorylate and activate Src. As such, PTP-alpha affects transformation and tumourigenesis, inhibition of proliferation and cell cycle arrest, mitotic activation of Src, integrin signalling, neuronal differentiation and outgrowth, and ion channel activity .
Mast/stem cell growth factor receptor (SCGF_receptor)
Type: Family

Mast/stem cell growth factor receptor (Kit) is a receptor protein-tyrosine kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity .
Protein kinase C, theta (PKC_theta)
Type: Family

Protein kinase C (PKC) theta is classified as a novel PKC (nPKC). PKC theta is involved in T-cell activation and survival .

The N-terminal regulatory domain of nPKC consists of a C2 domain follows by a double C1 domain (C1A and C1B). The C2 domain does not respond to calcium which makes nPKC diacylglycerol-sensitive but calcium-independent .

PKC is a family of serine- and threonine-specific protein kinases that depend on lipids for activity. They can be activated by calcium but have a requirement for the second messenger diacylglycerol . Members of this family play key regulatory roles in various cellular processes. Currently, there are ten isoforms of PKC which can be classified into classical (alpha, beta I, beta II, gamma), novel (delta, epsilon, eta, theta) and atypical (zeta, iota/lambda) types based on their primary structure and biochemical characteristics . All PKCs contain a C-terminal kinase domain and an N-terminal regulatory domain.
Aminomethyltransferase superfamily (TrmE/GcvT-like)
Type: Homologous_superfamily

This entry represents an α/β domain found in GTP-binding protein TrmE (N-terminal domain) , domain 1 of glycine cleavage T-protein (also known as aminomethyltransferase) , iron-sulfur cluster assembly factor IBA57 and related proteins.

TrmE is a guanine nucleotide-binding protein conserved between bacteria and eukaryotes. It is involved in the modification of uridine bases at the first anticodon (wobble) position of tRNAs. The N-terminal portion of the protein is necessary for mediating dimer formation within the protein .
AH/BAR domain superfamily (AH/BAR_dom_sf)
Type: Homologous_superfamily

This superfamily represents a structural domain which consists of three α-helices, including the arfaptin homology (AH) domain and the BAR (Bin-Amphiphysin-Rvs) domain.

The arfaptin homology (AH) domain is a protein domain found in a range of proteins, including arfaptins, protein kinase C-binding protein PICK1 and mammalian 69kDa islet cell autoantigen (ICA69) . The AH domain of arfaptin has been shown to dimerise and to bind Arf and Rho family GTPases , including ARF1, a small GTPase involved in vesicle budding at the Golgi complex and immature secretory granules. The AH domain consists of three α-helices arranged as an extended antiparallel α-helical bundle. Two arfaptin AH domains associate to form a highly elongated, crescent-shaped dimer .

Members of the Amphiphysin protein family are key regulators in the early steps of endocytosis, involved in the formation of clathrin-coated vesicles by promoting the assembly of a protein complex at the plasma membrane and directly assist in the induction of the high curvature of the membrane at the neck of the vesicle. Amphiphysins contain a characteristic domain, known as the BAR (Bin-Amphiphysin-Rvs) domain, which is required for their
in vivo
function and their ability to tubulate membranes .
The crystal structure of these proteins suggest the domain forms a crescent-shaped dimer of a three-helix coiled coil with a characteristic set of conserved hydrophobic, aromatic and hydrophilic amino acids. Proteins containing this domain have been shown to homodimerise, heterodimerise or, in a few cases, interact with small GTPases.
Peptidase M4/M1, CTD superfamily (Peptidase_M4/M1_CTD_sf)
Type: Homologous_superfamily

This superfamily represents an α-helix-bundled C-terminal domain (CTD) found in peptidases M4 and M1 family members . Both M1 and M4 metallopeptidases belong to the MEROPS peptidase family clan MA(E).
Acetolactate synthase/Transcription factor NikR, C-terminal (Acetolactate_synth/TF_NikR_C)
Type: Homologous_superfamily

This superfamily represent the C-terminal domain of the small subunit of acetolactate synthase and the C-terminal domain of the NikR, which is a transcription factor that regulates nickel uptake.
Piezo family (Piezo)
Type: Family

Piezo ('piesi' meaning pressure in Greek) proteins are pore-forming subunits of mechanically-activated channels . Expressing the proteins in mammalian cell lines has been shown to induce large mechanically-activated cationic currents . In Drosophila, they have been shown to be involved in sensing noxious mechanical stimuli, and plays a major role in nociception (response to strong or painful touch) . It is required for maintaining the mechanosensitivity of tarsal bristle mechanosensors . Piezo has been linked to Alzheimer disease in humans .
Neocarzinostatin-like (Neocarzinostatin-like)
Type: Homologous_superfamily

Neocarzinostatin (NCS) is a member of the macromolecular antitumour antibiotic family. NCS consists of two components, a polypeptide (apo-NCS) and a nonprotein chromophore. The crystal structure of NCS is similar to that of the related chromoproteins actinoxanthin and macromomycin .
Protein kinase C, epsilon (PKC_epsilon)
Type: Family

Protein kinase C, epsilon is a novel type of protein kinase C (nPKC). PKC epsilon plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion , motility, migration and cell cycle, functions in neuron growth and ion channel regulation , and is involved in immune response , cancer cell invasion and regulation of apoptosis .

The N-terminal regulatory domain of nPKC consists of a C2 domain follows by a double C1 domain (C1A and C1B). The C2 domain does not respond to calcium which makes nPKC diacylglycerol-sensitive but calcium-independent .

PKC is a family of serine- and threonine-specific protein kinases that depend on lipids for activity. They can be activated by calcium but have a requirement for the second messenger diacylglycerol . Members of this family play key regulatory roles in various cellular processes. Currently, there are ten isoforms of PKC which can be classified into classical (alpha, beta I, beta II, gamma), novel (delta, epsilon, eta, theta) and atypical (zeta, iota/lambda) types based on their primary structure and biochemical characteristics . All PKCs contain a C-terminal kinase domain and an N-terminal regulatory domain.
PRC-barrel domain (PRC-brl_dom)
Type: Domain

The PRC-barrel is an all β-barrel domain found in photosystem reaction centre subunit H of the purple bacteria and RNA metabolism proteins of the RimM group. PRC-barrels are approximately 80 residues long, and found widely represented in bacteria, archaea and plants. This domain is also present at the carboxyl terminus of the pan-bacterial protein RimM, which is involved in ribosomal maturation and processing of 16S rRNA. A family of small proteins conserved in all known euryarchaea are composed entirely of a single stand-alone copy of the domain, which play an essential role in archaeal FtsZ-based cell division . These proteins have been renamed as CdpB1 and CdpB2 .
Transforming protein C-ets-2 (Transform_prot_C-ets-2)
Type: Family

C-ets-2, a proto-oncogene and transcription factor, is a member of the ets gene family. It has amino acid similarity to the v-ets oncogene of the avian leukemia virus, E26 . Human and mouse C-ets-2 has been shown to have a role in skeletal development .
Nicotinate-nucleotide pyrophosphorylase/Putative pyrophosphorylase ModD (NadC/ModD)
Type: Family

Proteins in this family includes nicotinate-nucleotide pyrophosphorylase (

, also known as quinolinate phosphoribosyl transferases) and putative pyrophosphorylase ModD.

Nicotinate-nucleotide pyrophosphorylase is a type II phosphoribosyltransferase which provides the
de novo
source of nicotinate mononucleotide (NAMN) for NAD biosynthesis in both prokaryotes and eukaryotes . Human quinolinate phosphoribosyltransferase (also known as hQPRTase) is involved in the catabolism of quinolinic acid (QA) . Elevation of QA levels in the brain has been linked to the pathogenesis of a range of neurodegenerative disorders .

ModD is found with molybdenum transport genes modABC in Rhodobacter capsulatus. However, disruption of modD causes only a 4-fold (rather than 500-fold for modA, modB, modC) change in the external molybdenum concentration required to suppress an alternative nitrogenase . ModD proteins are highly similar to nicotinate-nucleotide pyrophosphorylase (also called quinolinate phosphoribosyltransferase). Their function is unknown.
1-aminocyclopropane-1-carboxylate deaminase/D-cysteine desulfhydrase (ACCD_DCysDesulf)
Type: Family

This entry represents the 1-aminocyclopropane-1-carboxylate deaminase/D-cysteine desulfhydrase family. Proteins in this family include deaminase, D-cysteine desulfhydrase, phenylserine dehydratase and L-cysteate sulfo-lyase.

1-aminocyclopropane-1-carboxylate deaminase (

) catalyses a cyclopropane ring-opening reaction, the irreversible conversion of 1-aminocyclopropane-1-carboxylate (ACC) to ammonia and alpha-ketobutyrate . Some plant growth-promoting rhizobacteria can produce 1-aminocyclopropane-1-carboxylate deaminase to enhance plant growth .

D-cysteine desulfhydrase (d-CDes) (

) catalyses the alpha, beta-elimination reaction of D-cysteine and of several D-cysteine derivatives. The Escherichia coli d-CDes catalyses D-cysteine into pyruvate, H2S, and NH3 . The physiological function of bacterial d-CDes is not clear.
D-aminopeptidase/lipoprotein domain superfamily (D_amino_pept/lipop_sf)
Type: Homologous_superfamily

Beta-Lactam antibiotics interfere with the biosynthesis of peptidoglycans in the bacterial cell wall by inactivating the penicillin-binding proteins DD-transpeptidases. Bacterial resistance to beta-lactam occurs through the synthesis of beta-lactmases that hydrolyse beta-lactam rings. D-aminopeptidase (DAP; peptidase family S12) is inhibited by beta-lactam antibiotics, and shares a low sequence identity with class C beta-lactamases and R61 DD-carboxypeptidase. DAP consists of three domains: the N-terminal domain A contains catalytic residues and displays a β-lactamase-like fold (

), domains B (middle) and C (C-terminal) domains are structurally similar, displaying an eight-stranded β barrel . Domain C is responsible for substrate and inhibitor specificity.

This superfamily represents a structurally similar domain to domains B and C of D-aminopeptidase. Proteins in this entry include D-aminopeptidases and some uncharacterised hypothetical lipoproteins from Streptococcus.
Saccharopine dehydrogenase [NAD(+), L-lysine-forming] (Lys1)
Type: Family

Saccharopine dehydrogenase [NAD(+), L-lysine-forming] (Lys1) catalyses the conversion of saccharopine to L-lysine, which is the final step in the lysine biosynthesis pathway .
Two partner secretion pathway transporter (TPS)
Type: Family

Proteins in this family are transporter proteins that are members or probable members of the two partner secretion pathway (TPS). In Gram-negative bacteria, TPS is used for the secretion of large, mostly virulence-related proteins. In this family, filamentous hemagglutinin transporter protein FhaC (TpsB transporter) from Bordetella pertussis mediates the secretion of major adhesin filamentous hemagglutinin (FHA) , while outer membrane transporter protein IbpB (TpsB transporter) from Haemophilus somnus mediate the secretion of protein IbpA (high molecular weight immunoglobulin-binding protein).
Glutamate synthase large subunit-like protein, bacteria (YerD)
Type: Family

Proteins in this family contain a domain similar to the large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) central domain. They contain the FMN-binding domain with a β/α barrel topology and the enzyme 3Fe-4S cluster. However, their function is still not clear.
Hepatocyte growth factor (Hepatocyte_GF)
Type: Family

Hepatocyte growth factor (HGF) is an activating ligand of the tyrosine kinase receptor Met. It activates Met by binding and promoting its dimerisation. This activation has been linked to promoting the invasive growth of many tumour types . HGF acts as growth factor for a broad spectrum of tissues and cell types and has no detectable protease activity .

Defects in HGF are the cause of deafness autosomal recessive type 39 (DFNB39). A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information .