SII-SWORD/CoKE huggingface dataset:
V-D-J recombination activating protein 2 (RAG2)
Type: Family

The variable portion of the genes encoding immunoglobulins and T cell receptors are assembled from component V, D, and J DNA segments by a site-specific recombination reaction termed V(D)J recombination. V(D)J recombination is targeted to specific sites on the chromosome by recombination signal sequences (RSSs) that flank antigen receptor gene segments. The RSS consists of a conserved heptamer (consensus, 5'-CACAGTG-3') and nonamer (consensus, 5'-ACAAAAACC-3') separated by a spacer of either 12 or 23 bp. Efficient recombination occurs between a 12-RSS and a 23-RSS, a restriction known as the 12/23 rule.

V(D)J recombination can be divided into two phases, DNA cleavage and DNA joining. DNA cleavage requires two lymphocyte-specific factors, the products of the recombination activating genes, RAG1 and RAG2, which together recognise the RSSs and create double strand breaks at the RSS-coding segment junctions . RAG-mediated DNA cleavage occurs in a synaptic complex termed the paired complex, which is constituted from two distinct RSS-RAG complexes, a 12-SC and a 23-SC (where SC stands for signal complex). The DNA cleavage reaction involves two distinct enzymatic steps, initial nicking that creates a 3'-OH between a coding segment and its RSS, followed by hairpin formation in which the newly created 3'-OH attacks a phosphodiester bond on the opposite DNA strand. This generates a blunt, 5' phosphorylated signal end containing all of the RSS elements, and a covalently sealed hairpin coding end.
Plasmid replicase, bacterial (Plasmid_replicase_bac)
Type: Family

This is a family of bacterial plasmid DNA replication initiator proteins. These RepA proteins exist as monomers and dimers in equilibrium: monomers bind directly to repeated DNA sequences and thus activate replication; dimers repress repA transcription by binding an inversely repeated DNA operator. Dimer dissociation can occur spontaneously or may be mediated by Hsp70 chaperones. A similar RepA family of proteins found mainly in Escherichia coli is involved in plasmid replication (see

).
Divalent ion tolerance protein, CutA (Ion_tolerance_CutA)
Type: Family

The CutA family of proteins which exhibit ion tolerance are found in a large variety of species . In E.Coli, two operons on the cutA locus contain genes that encode three proteins, CutA1, CutA2 and CutA3. CutA1 proteins are found in the cytoplasm while CutA2 (50kDa) and CutA3 (24kDa) are located in the inner membrane. Although the role of E. Coli CutA1 is not clear, studies on E. coli cutA locus describe some mutations that lead to an increase in copper sensitivity, thus suggesting a role in ion tolerance .

To date, the structure of CutA proteins from several species have been solved . The crystal structures of the E.Coli and rat CutA1 proteins show both these proteins to be trimeric in the crystal as well as in solution.Trimerisation seems to supported by the formation of β sheets between the subunit. This trimeric structure suggests the protein may be involved in signal transduction due to architectural similarities with PII signal transducer proteins .
Recent studies propose that mammalian CutA1 in the neuronal cell membrane acts as an anchor for acetylcholinesterase (AChE)1 .
Folate-biopterin transporter (FBT)
Type: Family

This entry includes folate-biopterin transporters (FBTs) from blue-green algae and plants, including Slr0642 protein from Synechocystis and its plastidial orthologue At2g32040 from Arabidopsis . Both Slr0642 protein and At2g32040 mediate folate monoglutamate transport involved in tetrahydrofolate biosynthesis. However, this entry also includes 7 other Arabidopsis FBT proteins that lack conserved critical residues and may not have folate or pterin transport activity .
Mlo-related protein (Mlo)
Type: Family

The Mlo-related proteins are a family of plant integral membrane proteins, first discovered in barley. Mutants lacking wild-type Mlo proteins show broad spectrum resistance to the powdery mildew fungus, and dysregulated cell death control, with spontaneous cell death in response to developmental or abiotic stimuli. Thus wild-type Mlo proteins are thought to be inhibitors of cell death whose deficiency lowers the threshold required to trigger the cascade of events that result in plant cell death.
Phosphotyrosyl phosphatase activator, PTPA (Phstyr_phstse_ac)
Type: Family

Phosphotyrosyl phosphatase activator (PTPA, also known as protein phosphatase 2A activator) proteins stimulate the phosphotyrosyl phosphatase (PTPase) activity of the dimeric form of protein phosphatase 2A (PP2A). PTPase activity in PP2A (in vitro) is relatively low when compared to the better recognised phosphoserine/ threonine protein phosphorylase activity. It also reactivates the serine/threonine phosphatase activity of an inactive form of PP2A. The specific biological role of PTPA is unknown. PTPA has been suggested to play a role in the insertion of metals to the PP2A catalytic subunit (PP2Ac) active site, to act as a chaperone, and more recently, to have peptidyl prolyl cis/trans isomerase activity that specifically targets human PP2Ac . Together, PTPA and PP2A constitute an ATPase and it has been suggested that PTPA alters the relative specificity of PP2A from phosphoserine/phosphothreonine substrates to phosphotyrosine substrates in an ATP-hydrolysis-dependent manner. Basal expression of PTPA depends on the activity of a ubiquitous transcription factor, Yin Yang 1 (YY1). The tumour suppressor protein p53 can inhibit PTPA expression through an unknown mechanism that negatively controls YY1 .
BRO1 domain (BRO1_dom)
Type: Domain

The BRO1 domain is a protein domain of ~390 residues in length. It occurs in a number of eukaryotic proteins, such as yeast BRO1 and human PDCD6IP/Alix, which are involved in protein targeting to the vacuole or lysosome. The BRO1 domain of fungal and mammalian proteins binds with multivesicular body components (ESCRT-III proteins) such as yeast Snf7 and mammalian CHMP4b, and can function to target BRO1 domain-containing proteins to endosomes .

The BRO1 domain has a boomerang shape composed of 14 α-helices and 3 β-sheets. It contains a TPR-like substructure in the central part . The C terminus is less conserved.
CcmE/CycJ protein (CcmE)
Type: Family

CcmE is the product of a cluster of Ccm genes that are necessary for cytochrome c biosynthesis in many prokaryotes and plant mitochondria . In E. coli, expression of these proteins is induced when the organisms are grown under anaerobic conditions with nitrate or nitrite as the final electron acceptor .
FAR1 DNA binding domain (FAR1_DNA_bnd_dom)
Type: Domain

Phytochrome A is the primary photoreceptor for mediating various far-red light-induced responses in higher plants. It has been found that the proteins governing this response, which include FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and FAR-RED-IMPAIRED RESPONSE1 (FAR1), are a pair of homologous proteins sharing significant sequence homology to mutator-like transposases. These proteins appear to be novel transcription factors, which are essential for activating the expression of FHY1 and FHL (for FHY1-like) and related genes, whose products are required for light-induced phytochrome A nuclear accumulation and subsequent light responses in plants.

The FRS (FAR1 Related Sequences) family of proteins share a similar domain structure to mutator-like transposases, including an N-terminal C2H2 zinc finger domain, a central putative core transposase domain, and a C-terminal SWIM motif (named after SWI2/SNF and MuDR transposases). It seems plausible that the FRS family represent transcription factors derived from mutator-like transposases .
SPX domain (SPX_dom)
Type: Domain

The SPX domain is named after SYG1/Pho81/XPR1 proteins. This 180 residue length domain is found at the amino terminus of a variety of proteins. In the yeast protein SYG1, the N terminus directly binds to the G- protein beta subunit and inhibits transduction of the mating pheromone signal suggesting that all the members of this family are involved in G-protein associated signal transduction. The C-terminal of these proteins often have an EXS domain (

) .

The N-termini of several proteins involved in the regulation of phosphate transport, including the putative phosphate level sensors PHO81 from Saccharomyces cerevisiae and NUC-2 from Neurospora crassa, are also members of this family . NUC-2 contains several ankyrin repeats (

).

Several members of this family are the XPR1 proteins: the xenotropic and polytropic retrovirus receptor confers susceptibility to infection with Murine leukemia virus (MLV) . The similarity between SYG1, phosphate regulators and XPR1 sequences has been previously noted, as has the additional similarity to several predicted proteins, of unknown function, from Drosophila melanogaster, Arabidopsis thaliana, Caenorhabditis elegans, Schizosaccharomyces pombe, and Saccharomyces cerevisiae . In addition, given the similarities between XPR1 and SYG1 and phosphate regulatory proteins, it has been proposed that XPR1 might be involved in G-protein associated signal transduction and may itself function as a phosphate sensor .
Transposase, MuDR, plant (Transposase_MuDR)
Type: Domain

The plant MuDR transposase domain is present in plant (and some fungal) proteins that are presumed to be the transposases for Mutator transposable elements . The function of these proteins is unknown.
SBP domain (SBP_dom)
Type: Domain

SBP (for SQUAMOSA-pROMOTER BINDING PROTEIN) domain is a sequence specific DNA-binding domain found in plant proteins . Members of family probably function as transcription factors involved in the control of early flower development . They share a highly conserved DNA-binding domain that contains two zinc-binding sites. Among the 11 possible ligands for the zinc atoms that are conserved in the SBP zinc finger, only 8 are used. The SBP zinc finger follows the general pattern C-x4-C-x16-C-x2-[HC]-x15-C-x2-C-x3-H-x11-C. Three other histidines are well conserved but not involved in zinc binding .

In vitro experiments show that the SBP zinc finger preferentially binds the consensus sequence -TNCGTACAA- . However, little is known of the physiological functions of these putative transcriptional regulators beyond their ability to bind DNA.

The solution structure of the SBP zinc finger has been solved . The first four Cys or His coordinate one zinc ion and the last four coordinate the other. It can be viewed as two structural subdomains, each subdomain containing a single zinc-binding pocket. The N-terminal subdomain consists of two short α helices whereas the C-terminal one contains a three-stranded antiparallel β-sheet.
Poxvirus E5R (Poxvirus_E5R)
Type: Family

This family of poxvirus proteins includes Protein OPG067 (also known as Protein E5). It is found in cytoplasmic sites of viral DNA replication . The presence of BEN domains suggests a possible role in organisation of viral DNA during replication or transcription .
Protein of unknown function DUF244 (DUF244)
Type: Family

Many of the proteins in this entry are Borrelia burgdorferi plasmid proteins of unknown function.
Respiratory synctial virus non-structural protein NS2 (RSV_NS2)
Type: Family

The molecular structure and function of the NS2 protein is not known. However, mutants lacking the NS2 grow at slower rates when compared to the wild-type yet NS2 is not essential for viral replication .
Astrovirus capsid protein, inner core domain (Astro_capsid_N)
Type: Domain

This entry represents the inner core nucleoplasmin-like domain of astrovirus capsid protein. The capsid protein (CP) undergoes proteolytic maturation to generate infectious particles. The CP is composed of several domains, including a highly basic N-terminal domain, a core domain, a spike domain, and a C-terminal acidic domain . The core domain is composed of two domains named inner and outer core domain, respectively

. This entry represents the inner core domain.

Astroviruses are a leading cause of viral diarrhea in young children, immunocompromised individuals, and the elderly. The astrovirus genome is apparently organised with nonstructural proteins encoded at the 5' end and structural proteins at the 3' end . Proteins in this family are encoded by astrovirus ORF2, one of the three astrovirus ORFs (1a, 1b, 2). The proteins contain a viral RNA-dependent RNA polymerase motif . The 87kDa precursor polyprotein undergoes an intracellular cleavage to form a 79kDa protein. Subsequently, extracellular trypsin cleavage yields the three proteins forming the infectious virion .
Ion-translocating oxidoreductase NqrB/RnfD (NqrB/RnfD)
Type: Family

This family of proteins describes the Nqr2 (NqrB) subunit of the bacterial 6-subunit sodium-translocating NADH-ubiquinone oxidoreductase (i.e. a respiration linked sodium pump). In Vibrio cholerae, it negatively regulates the expression of virulence factors through inhibiting (by an unknown mechanism) the transcription of the transcriptional activator ToxT .

The family also includes RnfD, which is a subunit of the Rnf complex, a ferredoxin:NAD+ oxidoreductase that appears to translocate different ions (protons or sodium) in different bacteria . The similarity of RnfD to NADH-ubiquinone oxidoreductases was previously noted .
UL49-related protein (UL49)
Type: Family

UL49 proteins are present in the viral tegument at the surface of the nucleocapsid . Many of the nonconserved tegument proteins of alpha-herpes viruses play important roles during different steps of the viral replication cycle, such as the shutoff of host cell functions by the vhs protein encoded by UL41 and the transcriptional activation of viral immediate-early genes by the UL48 gene product, VP16. UL49 of Human herpesvirus 1 (HHV-1) has been shown to directly interact with VP16. The UL49 gene products of HHV-1 and Bovine herpesvirus 1 exhibit virus-independent intercellular trafficking of unknown biological function but are dispensable for productive viral replication.

Envelope glycoprotein M (gM) and the complex formed by glycoproteins E (gE) and I (gI) are involved in the secondary envelopment of Suid herpesvirus 1 (Pseudorabies virus, PrV) particles in the cytoplasm of infected cells. In the absence of the gE-gI complex and gM, envelopment is blocked and capsids surrounded by tegument proteins accumulate in the cytoplasm. The cytoplasmic domains of gE and gM specifically interact with the C-terminal part of the UL49 gene product of PrV suggesting a role for the protein in secondary envelopment during herpesvirus virion maturation .
CAT RNA-binding domain (CAT_RNA-bd_dom)
Type: Domain

This RNA binding domain is found at the amino terminus of transcriptional antitermination proteins such as BglG, SacY and LicT. These proteins control the expression of sugar metabolising operons in Gram-positive and Gram-negative bacteria. This domain has been called the CAT (Co-AntiTerminator) domain. It binds as a dimer to short Ribonucleotidic Anti-Terminator (RAT) hairpin, each monomer interacting symmetrically with both strands of the RAT hairpin . In the full-length protein, CAT is followed by two phosphorylatable PTS regulation domains that modulate the RNA binding activity of CAT. Upon activation, the dimeric proteins bind to RAT targets in the nascent mRNA, thereby preventing abortive dissociation of the RNA polymerase from the DNA template .
EXS, C-terminal (EXS_C)
Type: Domain

The EXS domain is named after ERD1/XPR1/SYG1 and proteins containing this motif include the C-terminal of the SYG1 G-protein associated signal transduction protein from Saccharomyces cerevisiae, and sequences that are thought to be Murine leukemia virus (MLV) receptors (XPR1. The N-terminal of these proteins often have an SPX domain (

) .

While the N-terminal is thought to be involved in signal transduction, the role of the C-terminal is not known. This region of similarity contains several predicted transmembrane helices. This family also includes the ERD1 (ERD: ER retention defective) S. cerevisiae proteins. ERD1 proteins are involved in the localization of endogenous endoplasmic reticulum (ER) proteins. Erd1 null mutants secrete such proteins even though they possess the C-terminal HDEL ER lumen localization label sequence. In addition, null mutants also exhibit defects in the Golgi-dependent processing of several glycoproteins, which led to the suggestion that the sorting of luminal ER proteins actually occurs in the Golgi, with subsequent return of these proteins to the ER via `salvage' vesicles .
Plus-3 domain (Plus-3_dom)
Type: Domain

The yeast Paf1 complex consists of Pfa1, Rtf1, Cdc73, Ctr9, and Leo1. The complex regulates histone H2B ubiquitination, histone H3 methylation, RNA polymerase II carboxy-terminal domain (CTD) Ser2 phosphorylation, and RNA 3' end processing. The conservation of Paf1 complex function in higher eukaryotes has been confirmed in human cells, Drosophila and Arabidopsis. The Plus3 domain spans the most conserved regions of the Rtf1 protein and is surrounded by regions of low complexity and coiled-coil propensity . It contains only a limited number of highly conserved amino acids, among which are three positively charged residues that gave the Plus3 domain its name. The capacity to bind single-stranded DNA is at least one function of the Plus3 domain .

The plus-3 domain is about 90 residues in length and is often found associated with the GYF domain (

). The Plus3 domain structure consists of six α-helices intervened by a sequence of six β-strands in a mixed α/β topology. β-strands 1, 2, 5, and 6 compose a four-stranded antiparallel β-sheet with a β-hairpin insertion formed by strands 3 and 4. The N-terminal helices α1-α3 and C-terminal helix α6 pack together to form an α subdomain, while the β-strands and the small 3(10) helix α4 form a β-subdomain. The two subdomains pack together to form a compact, globular protein .
Tubulin-tyrosine ligase/Tubulin polyglutamylase (TTL/TTLL_fam)
Type: Family

Tubulins and microtubules are subjected to several post-translational modifications of the carboxy-terminal end of most major forms of tubulins has been extensively analysed. This modification cycle involves a specific carboxypeptidase and the activity of the tubulin-tyrosine ligase (TTL) and the tubulin polyglutamylase (TTLL) . Tubulin-tyrosine ligase (TTL) catalyses the ATP-dependent post-translational addition of a tyrosine to the carboxy terminal end of detyrosinated alpha-tubulin. Tubulin polyglutamylase (such as TTLL10) can modify both tubulin and non-tubulin proteins, generating side chains of glycine on the γ-carboxyl groups of specific glutamate residues of target proteins . Tubulin polyglutamylation may be involved in the organisation of the neuronal microtubule network, in centriole stability, axoneme motility and mitosis .
TB2/DP1/HVA22 (TB2_DP1_HVA22)
Type: Family

This family includes members from a wide variety of eukaryotes and includes Receptor expression-enhancing proteins (REEPs), its homologues from fungi Yop1 and similar sequences from plants. REEP/DP1/Yop1 family of proteins are involved in the control of endoplasmic reticulum organisation and mutations in some members of this family are associated with inherited diseases like Hereditary spastic paraplegias (HSPs) . REEP5, also known as TB2/DP1 (deleted in polyposis) protein , plays an essential role in heart function and development by regulating the organization and function of the sarcoplasmic reticulum in cardiomyocytes . In human is deleted in severe forms of familial adenomatous polyposis, an autosomal dominant oncological inherited disease .

The family also includes the plant protein of known similarity to TB2/DP1, the HVA22 abscisic acid-induced protein, which is thought to be a regulatory protein .
CagE, TrbE, VirB component of type IV transporter system (CagE_TrbE_VirB)
Type: Family

This family includes the Helicobacter pylori protein CagE (

), which together with other proteins from the cag pathogenicity island (PAI), encodes a type IV transporter secretion system. It is the ATPase component of the type IV secretion system Cag (Cag-T4SS) that may acts as a molecular motor to provide the energy that is required for the export of proteins. It is essential for pathogenesis in Helicobacter pylori induced gastritis and peptic ulceration , being required for CagA translocation and induction of IL-8 in host gastric epithelial cells . Indeed, the expression of the cag PAI has been shown to be essential for stimulating human gastric epithelial cell apoptosis in vitro . CagE plays a key role in Cag-T4SS pilus biogenesis, especially in the localization and stabilization of the pilus-associated components CagI, CagL and the surface protein CagH and it is also critical for assembly of the entire cytoplasmic portion of the Cag inner membrane complex (IMC) .

Similar type IV transport systems are also found in other bacteria. This family includes proteins from the trb and Vir conjugal transfer systems in
Agrobacterium tumefaciens and homologues of VirB proteins from other species.
Pup ligase/deamidase (Pup_ligase/deamidase)
Type: Family

Pupylation is a novel protein modification system found in some bacteria . This entry represents two related groups of proteins involved in this system. Pup ligases, such as PafA, conjugate the prokaryotic ubiquitin-like protein Pup to lysine residues in target proteins, marking them for degradation . Pup deamidases, such as PafD, catalyse the deamidation of the Pup C-terminal glutamine to glutamate, thereby rendering the protein competent for conjugation . It has been suggested that proteins in this entry are related to gamma-glutamyl-cysteine synthetases .
Vanadium/alternative nitrogenase delta subunit (V/Nase_d_su)
Type: Family

The nitrogenase complex

catalyses the conversion of molecular nitrogen to ammonia (nitrogen fixation). The complex is hexameric, consisting of 2 alpha, 2 beta, and 2 delta subunits.
Glycoside-hydrolase family GH114, TIM-barrel domain (GH114_TIM-barrel)
Type: Domain

Proteins in this entry are recognised as members of a glycosyl-hydrolase family, number 114. It is endo-alpha-1,4-polygalactosaminidase, a rare enzyme. It is proposed to be TIM-barrel, the most common structure amongst the catalytic domains of glycosyl-hydrolases .
Vacuolar fusion protein Mon1 (Mon1)
Type: Family

Members of this family have been called SAND proteins although these proteins do not contain a SAND domain. In Saccharomyces cerevisiae, Mon1 is part of the Mon1-Ccz1 complex that acts as the guanine nucleotide exchange factor (GEF) of the yeast Rab7 GTPase Ypt7 . The Mon1/Ccz1 complex is conserved in eukaryotic evolution and members of this family (previously known as DUF254) are distant homologues to domains of known structure that assemble into cargo vesicle adapter (AP) complexes .
Meiotic recombination protein Rec114 (Meiotic_Rec114)
Type: Family

This entry includes budding yeast Rec114 protein and its homologue, Rec7, from S. pombe. They are required for meiotic intragenic recombination but not for mitotic recombination .
Type IV secretion system CagA exotoxin (IVSec_CagA)
Type: Family

Helicobacter pylori makes use of a type IV secretion system similar in mechanism to the conjugation machine of Agrobacterium tumefaciens . These machines secrete three different types of substrate: DNA conjugation intermediates, as in A. tumefaciens; multimeric proteins such as the pertussis toxin of Bordetella pertussis; and the CagA protein of H. pylori. CagA has been linked to the more severe forms of gastric ulcers and duodenal cancers . Both CagA and the secretion system apparatus are encoded in the large pathogenicity island, termed cag , possessed by the malignant disease-causing type I bacterial strains.

The CagA exotoxin is encoded in the last portion of the island, and mutants lacking the gene fail to induce IL-8 secretion, and to activate NF-kappa-B in vivo . CagA is believed to have a similar function to EPEC type III secreted effectors; both are tyrosine-phosphorylated once translocated into the target cell , and allow engulfment by the host via rearrangement of the actin cytoskeleton.