SII-SWORD/CoKE huggingface dataset:
RTX toxin determinant A (RTX_toxin_determinant-A)
Type: Family

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior . Four principal exotoxin secretion systems have been described. In the type II and IV secretion systems, toxins are first exported to the periplasm by way of a cleaved N-terminal signal sequence; a second set of proteins is used for extracellular transport (type II), or the C terminus of the exotoxin itself is used (type IV). Type III secretion involves at least 20 molecules that assemble into a needle; effector proteins are then translocated through this without need of a signal sequence. In the Type I system, a complete channel is formed through both membranes, and the secretion signal is carried on the C terminus of the exotoxin.

The RTX (repeats in toxin) family of cytolytic toxins belong to the Type I secretion system, and are important virulence factors in Gram-negative bacteria, such as Escherichia coli (

), Actinobacillus pleuropneumoniae (

) and Kingella kingae (

). They consist of a hydrophobic pore-forming domain at the N-terminal that harbors four putative transmembrane α-helices, a typical glycine-rich repeats segment and a C-terminal signal sequence . The glycine-rich repeats are essential for binding calcium, and are critical for the biological activity of the secreted toxins . They can be divided into two different groups, (i) hemolysins, which cause cause the lysis of erythrocytes and exhibit toxicity towards a wide range of cell types from various species; and (ii) leukotoxins, that exhibit narrow cell type and species specificity due to cell-specific binding through the beta2-integrins expressed on the cell surface of leukocytes . All RTX toxin operons exist in the order rtxCABD, RtxA protein being the structural component of the exotoxin, both RtxB and D being required for its export from the bacterial cell; RtxC is an acyl-carrier-protein-dependent acyl-modification enzyme, required to convert RtxA to its active form .

Escherichia coli haemolysin (HlyA) is often quoted as the model for RTX toxins. Recent work on its relative rtxC gene product HlyC has revealed that it provides the acylation aspect for post-translational modification of two internal lysine residues in the HlyA protein. To cause pathogenicity, the HlyA toxin must first bind Ca2+ ions to the set of glycine-rich repeats and then be activated by HlyC . This has been demonstrated both
in vitro
and
in vivo
.
RTX toxin-activating protein C, bacteria (RTX_toxin-activating_protC_bac)
Type: Family

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior . Four principal exotoxin secretion systems have been described. In the type II and IV secretion systems, toxins are first exported to the periplasm by way of a cleaved N-terminal signal sequence; a second set of proteins is used for extracellular transport (type II), or the C terminus of the exotoxin itself is used (type IV). Type III secretion involves at least 20 molecules that assemble into a needle; effector proteins are then translocated through this without need of a signal sequence. In the Type I system, a complete channel is formed through both membranes, and the secretion signal is carried on the C terminus of the exotoxin.

The RTX (repeats in toxin) family of cytolytic toxins belong to the Type I secretion system, and are important virulence factors in Gram-negative bacteria. As well as the C-terminal signal sequence, several glycine-rich repeats are also found. These are essential for binding calcium, and are critical for the biological activity of the secreted toxins . All RTX toxin operons exist in the order rtxCABD, RtxA protein being the structural component of the exotoxin, both RtxB and D being required for its export from the bacterial cell; RtxC is an acyl-carrier-protein-dependent acyl- modification enzyme, required to convert RtxA to its active form .

Escherichia coli haemolysin (HlyA) is often quoted as the model for RTX toxins. Recent work on its relative rtxC gene product HlyC has revealed that it provides the acylation aspect for post-translational modification of two internal lysine residues in the HlyA protein. Other residues, including His23 and two conserved tyrosine residues, also appear to be important .
Actin family (Actin)
Type: Family

Actin is a ubiquitous protein involved in the formation of filaments that are major components of the cytoskeleton. These filaments interact with myosin to produce a sliding effect, which is the basis of muscular contraction and many aspects of cell motility, including cytokinesis. Each actin protomer binds one molecule of ATP and has one high affinity site for either calcium or magnesium ions, as well as several low affinity sites. Actin exists as a monomer in low salt concentrations, but filaments form rapidly as salt concentration rises, with the consequent hydrolysis of ATP. Actin from many sources forms a tight complex with deoxyribonuclease (DNase I) although the significance of this is still unknown. The formation of this complex results in the inhibition of DNase I activity, and actin loses its ability to polymerise. It has been shown that an ATPase domain of actin shares similarity with ATPase domains of hexokinase and hsp70
proteins .

In vertebrates there are three groups of actin isoforms: alpha, beta and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exists in most cell types as components of the cytoskeleton and as mediators of internal cell motility. In plants there are many isoforms which are probably involved in a variety of functions such as cytoplasmic streaming, cell shape determination, tip growth, graviperception, cell wall deposition, etc.

Recently some divergent actin-like proteins have been identified in several species. These proteins include centractin (actin-RPV) from mammals, fungi yeast ACT5, Neurospora crassa ro-4 and Pneumocystis carinii, which seems to be a component of a multi-subunit centrosomal complex involved in microtubule based vesicle motility (this subfamily is known as ARP1); ARP2 subfamily, which includes chicken ACTL, Saccharomyces cerevisiae ACT2, Drosophila melanogaster 14D and Caenorhabditis elegans actC; ARP3 subfamily, which includes actin 2 from mammals, Drosophila 66B, yeast ACT4 and Schizosaccharomyces pombe act2; and ARP4 subfamily, which includes yeast ACT3 and Drosophila 13E.
Actin, conserved site (Actin_CS)
Type: Conserved_site

Actin is a ubiquitous protein involved in the formation of filaments that are major components of the cytoskeleton. These filaments interact with myosin to produce a sliding effect, which is the basis of muscular contraction and many aspects of cell motility, including cytokinesis. Each actin protomer binds one molecule of ATP and has one high affinity site for either calcium or magnesium ions, as well as several low affinity sites. Actin exists as a monomer in low salt concentrations, but filaments form rapidly as salt concentration rises, with the consequent hydrolysis of ATP. Actin from many sources forms a tight complex with deoxyribonuclease (DNase I) although the significance of this is still unknown. The formation of this complex results in the inhibition of DNase I activity, and actin loses its ability to polymerise. It has been shown that an ATPase domain of actin shares similarity with ATPase domains of hexokinase and hsp70 proteins .

In vertebrates there are three groups of actin isoforms: alpha, beta and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exists in most cell types as components of the cytoskeleton and as mediators of internal cell motility. In plants there are many isoforms which are probably involved in a variety of functions such as cytoplasmic streaming, cell shape determination, tip growth, graviperception, cell wall deposition, etc.
Helicase/polymerase/peptidase polyprotein, Calicivirus-type (Helic/Pol/Pept_Calicivir-typ)
Type: Family

Caliciviruses are positive-stranded ssRNA viruses that cause gastroenteritis . The calicivirus genome contains two open reading frames, ORF1 and ORF2 . ORF1 encodes a non-structural polypeptide, which has RNA helicase, cysteine protease and RNA polymerase activity. The cysteine peptidases of the Calciviruses belong to MEROPS peptidase families C3 (subfamilies A to G), C24, C28, C37 and C40. The regions of the poly-protein in which these activities lie are similar to proteins produced by the picornaviruses .
Calicivirus coat protein (Calicivirus_coat)
Type: Domain

Rabbit hemorrhagic disease virus (RHDV) which causes a highly contagious disease of wild and domestic rabbits belongs to the family Caliciviridae . The capsid protein self assembles to form an icosahedral capsid with a T=3 symmetry. It is about 38nm in diameter and consists of 180 capsid proteins. The capsid encapsulates the genomic RNA and VP2 proteins and attaches the virion to target cells by binding histo-blood group antigens present on gastroduodenal epithelial cells. The Shell domain (S domain) contains elements essential for the formation of the icosahedron. The Protruding domain (P domain) is divided into sub-domains P1 and P2. An hypervariable region in P2 is thought to play an important role in receptor binding and immune reactivity.

This entry represents a calicivirus coat protein.
DhaK domain (DhaK_dom)
Type: Domain

Dihydroxyacetone (Dha) kinases are a family of sequence-conserved enzymes that phosphorylate dihydroxyacetone, glyceraldehyde and other short-chain ketoses and aldoses. They can be divided into two groups according to the source of high-energy phosphate that they utilise, either ATP or phosphoenolpyruvate (PEP). The ATP-dependent forms are the two-domain Dha kinases (DAK), which occur in animals, plants and eubacteria. They consist of a Dha binding (K) and an ATP binding (L) domain. The PEP-dependent forms occur only in eubacteria and a few archaebacteria and consist of three subunits. Two subunits, DhaK and DhaL, are homologous to the K and L domains. Intriguingly, the ADP moiety is not exchanged for ATP but remains permanently bound to the DhaL subunit where it is rephosphorylated in situ by the third subunit, DhaM, which is homologous to the IIA domain of the mannose transporter of the bacterial PEP:sugar phosphotransferase system (PTS) .

The DhaK domain consists of two α/β-folds, each containing a six- stranded mixed β-sheet surrounded by six and three helices, respectively. Dha is bound in hemiaminal linkage to the imidazole nitrogen of an invariant histidine .
DhaL domain (DhaL_dom)
Type: Domain

Dihydroxyacetone (Dha) kinases are a family of sequence-conserved enzymes that phosphorylate dihydroxyacetone, glyceraldehyde and other short-chain ketoses and aldoses. They can be divided into two groups according to the source of high-energy phosphate that they utilise, either ATP or phosphoenolpyruvate (PEP). The ATP-dependent forms are the two-domain Dha kinases (DAK), which occur in animals, plants and eubacteria. They consist of a Dha binding (K) and an ATP binding (L) domain. The PEP-dependent forms occur only in eubacteria and a few archaebacteria and consist of three subunits. Two subunits, DhaK and DhaL, are homologous to the K and L domains. Intriguingly, the ADP moiety is not exchanged for ATP but remains permanently bound to the DhaL subunit where it is rephosphorylated in situ by the third subunit, DhaM, which is homologous to the IIA domain of the mannose transporter of the bacterial PEP:sugar phosphotransferase system (PTS) .

The DhaL domain consists of eight antiparallel α-helices arranged in an up-and-down geometry and aligned on a circle. This results in the formation of a helix barrel enclosing a deep pocket. The helices are amphipathic with the hydrophobic side chains directed into the pocket of the barrel and with the polar residues exposed. The nucleotide is bound on the top of the barrel .

The DhaL α helix barrel fold appears not only as a C-terminal domain in Dha kinases but also as an N-terminal domain in a family of two-domain proteins with unknown function. One representative example is YfhG of Lactococcus lactis .
Myosin, SH3 domain (SH3_Myosin)
Type: Domain

This entry represents the N-terminal in myosin proteins.

The myosin N-terminal SH3-like domain may mediate some aspect of the conformational communication that occurs within the myosin head during actin and nucleotide binding. Part of this effect may be mediated through interactions with the neck-associated essential light chains that are in close proximity to this portion of the head domain and also transiently interact with actin . The myosin N-terminal SH3-like domain comprises ~50 amino acids and forms a protruding, six-stranded, antiparallel, β-barrel domain with similarities to the SH3 domain .

Members of the myosin superfamily of actin-based motors act in a variety of cellular functions such as muscle contraction, cell and organelle movement, membrane trafficking, and signal transduction. Although myosin motor domains show a high degree of sequence conservation, the individual myosin classes are clearly defined by differences in the head structure. The N-terminal region of myosins from different classes varies greatly in length and amino acid composition among the individual members. Many myosins have an SH3-like domain at the N-terminal of the motor domain. This includes myosins in classes II, V, VI, XI, XXII and XXIV.
Double Cache domain 2 (Double_Cache_2)
Type: Domain

Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors.

This entry represents the double Cache domain 2 (dCache_2), which may be a result of single Cache domain 2 (sCache_2) duplication .
GYR motif (Gyr_motif)
Type: Conserved_site

The GYR motif is found in several Drosophila melanogaster proteins, in either single or multiple copies. Its function is unknown, however the presence of completely conserved tyrosine residues may suggest it could be a substrate for tyrosine kinases.
RUN domain (Run_dom)
Type: Domain

The RUN domain, named after RPIP8, unc-14 and NESCA, is organised into six conserved blocks (A-F), which constitute the 'core' of a globular structure tolerating insertions of considerable length between the conserved blocks . The RUN domain is found in one or two copies in several proteins that are linked particularly to the functions of GTPases in the Rap and Rab families. This domain is thought to be a specific effector of small GTPases, but in the case of many of RUN domains their specific partners and their roles need to be determined. RUN domains can be associated with TBC/rab GAP, FYVE, DENN, SH3, DAG/PE-binding, PLAT/LH2, PH or PX domains. The RUN domain may have a role in the interaction of various proteins with cytoskeletal filaments .

The predicted secondary structures of the RUN domain core indicate a predominantly α-fold .
PHP domain (PHP_dom)
Type: Domain

The PHP (Polymerase and Histidinol Phosphatase) domain has four conserved sequence motifs that contain invariant histidine and aspartate residues implicated in metal ion coordination. It is found in alpha-subunit of bacterial DNA polymerase III (

) and family X DNA polymerases in addition to histidinol phosphatase (

) . As part of DNA polymerases, the PHP domain was suggested to hydrolyse pyrophosphate . This family is often associated with an N-terminal region

. This domain has a distorted (α/β)7 barrel fold .
Cation-transporting P-type ATPase, N-terminal (ATPase_P-typ_cation-transptr_N)
Type: Domain

This entry represents the conserved N-terminal region found in several classes of cation-transporting P-type ATPases, including those that transport H
+
(

), Na
+
(

), Ca
2+
(

), Na
+
/K
+
(

), and H
+
/K
+
(

). In the H
+
/K
+
-and Na
+
/K
+
-exchange P-ATPases, this domain is found in the catalytic alpha chain. In gastric H
+
/K
+
-ATPases, this domain undergoes reversible sequential phosphorylation inducing conformational changes that may be important for regulating the function of these ATPases .

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.

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.
SKI-interacting protein SKIP, SNW domain (SKI-int_prot_SKIP_SNW-dom)
Type: Domain

SKIP (SKI-interacting protein) is an essential spliceosomal component and transcriptional coregulator, which may provide regulatory coupling of transcription initiation and splicing . SKIP was identified in a yeast 2-hybrid screen, where it was shown to interact with both the cellular and viral forms of SKI through the highly conserved region on SKIP known as the SNW domain . SKIP is now known to interact with a number of other proteins as well. SKIP potentiates the activity of important transcription factors, such as vitamin D receptor, CBF1 (RBP-Jkappa), Smad2/3, and MyoD. It works with Ski in overcoming pRb-mediated cell cycle arrest, and it is targeted by the viral transactivators EBNA2 and E7 .

This entry represents the SNW domain.
Cysteine-rich domain (Cys_rich_dom)
Type: Domain

This domain is usually found in two copies per protein. It contains up to four conserved cysteines. The group includes proteins characterised as: heterodisulphide reductase, subunit B (HrdB,

); lactate utilization protein A (LutA); Fe-S oxidoreductase; glycerol-3-phosphate dehydrogenase subunit C (Anaerobic GlpC); and glycolate oxidase iron-sulphur subunit (GlcF) .
RPEL repeat (RPEL_repeat)
Type: Repeat

RPEL repeat (RPxxxEL) containing proteins are found in a wide range of metazoan organisms. RPEL repeats have been shown to be required for unpolymerised actin binding and proteins containing RPEL repeats are able to modify cell shape and/or are important in the regulation of gene expression by the actin cytoskeleton. RPEL repeats can be found in association with the SAP motif, which could be involved in DNA binding .

Some proteins known to contain RPEL repeats are listed below:

Mammalian myocardin, heart-specific serum response factor (SRF) co- activator.

Vertebrate myocardin-related transcription factor A (MRTF-A or MAL), a signal-regulated SRF co-activator.

Vertebrate myocardin-related transcription factor B (MRTF-B).

Mammalian phosphatase and actin regulator 1 to 3.
YLP motif (YLP_motif)
Type: Conserved_site

The YLP motif is found in one or several copies in various Drosophila proteins. Its function is unknown, however the presence of completely conserved tyrosine residues and its presence in the human Erbb-2 and ErbB-4 receptor protein-tyrosine kinases (

) may suggest it could be a substrate for tyrosine kinases. ErbBs (1-4) are single-pass transmembrane proteins that activate a wide variety of signalling pathways, including those involved in proliferation, migration, differentiation, survival, and apoptosis; they are frequently misregulated in cancer . ErbB-2 is an essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. ErbB-4 specifically binds and is activated by neuregulins, NRG-2, NRG-3, heparin-binding EGF-like growth factor, betacellulin and NTAK .
DAPIN domain (DAPIN)
Type: Domain

The DAPIN (Domain in Apoptosis and INterferon response) domain is an 80-100- residue domain which is found in the N terminus of diverse vertebrate and vertebrate-specific viral proteins involved in apoptosis, cancer, inflammation, and immune response. The DAPIN domain can be found alone or in association with other domains like CARD, LRR, SPRY, Caspase or Zinc finger B-box. It has been proposed that the DAPIN domain might have an adaptor function, coupling apoptosis and immune disorders . It has been shown that the DAPIN domain is a protein-protein interaction domain capable of binding to other DAPIN domains .

Secondary structure predictions have identified the DAPIN domain as mostly α-helical and it has been suggested that it could belong to the DEATH- domain-fold superfamily, which includes the CARD, the DEATH domain (DD) and the DEATH effector domain (DED) .

The DAPIN domain has also been called pyrin domain, pyrin N-terminal homology domain (PYD) or PAAD (after the protein families pyrin, AIM, ASC death-domain- like) .
HIN-200/IF120x (HIN200/IF120x)
Type: Domain

This domain is found in one or two copies per protein, and is found associated with the PAAD/DAPIN domain

. The HIN domain recognises and interacts with the phosphate backbone of dsDNA in a sequence-independent manner .
Mago nashi protein (Mago_nashi)
Type: Family

This family was originally identified in Drosophila and called mago nashi, it is a strict maternal effect, grandchildless-like, gene . The protein is an integral member of the exon junction complex (EJC). The EJC is a multiprotein complex that is deposited on spliced mRNAs after intron removal at a conserved position upstream of the exon-exon junction, and transported to the cytoplasm where it has been shown to influence translation, surveillance, and localization of the spliced mRNA. It consists of four core proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP and is supposed to be a binding platform for more peripherally and transiently associated factors along mRNA travel. Mago and Y14 form a stable heterodimer that stabilizes the complex by inhibiting eIF4AIII's ATPase activity. Mago-Y14 heterodimer has been shown to interact with the cytoplasmic protein PYM, an EJC disassembly factor, and specifically binds to the karyopherin nuclear receptor importin 13 .

The human homologue has been shown to interact with an RNA binding protein, ribonucleoprotein rbm8 (

) . An RNAi knockout of the Caenorhabditis elegans homologue causes masculinization of the germ line (Mog phenotype) hermaphrodites, suggesting it is involved in hermaphrodite germ-line sex determination but the protein is also found in hermaphrodites and other organisms without a sexual differentiation.
Fungal ribotoxin (Fun_ribotoxin)
Type: Family

The fungal ribotoxins are a family of highly specific ribonucleases that inactivate the ribosome by cleavage of the 23-28S RNA of the large ribosomal subunit at a single phosphodiester bond. Cleavage abolishes the capacity of ribosomes to carry out protein synthesis by inhibiting elongation factor 1- dependent binding of aminoacyl-tRNA and GTP-dependent binding of elongation factor 2 to ribosomes. Mitogillin-like ribotoxins are among the most potent inhibitors of translation so far identified, and they have been investigated as potential anti-tumour agents, or components of immunotoxins . Members of this family include ribonuclease mitogillin, ribonuclease alpha-sarcin and ribonuclease clavin precursor proteins.