SII-SWORD/CoKE huggingface dataset:
RNA-directed RNA polymerase, luteovirus (RNA-dir_pol_luteovirus)
Type: Family

RNA-directed RNA polymerase (RdRp) (

) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage . It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear.
The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product .

The nucleotide sequence for the RNA of Potato leafroll virus (PLrV) has been determined . The sequence contains six large open reading frames (ORFs). The 5' coding region encodes two polypeptides of 28K and 70K, which overlap in different reading frames; it is suggested that the third ORF in the 5' block is translated by frameshift read through near the end of the 70K protein, yielding a 118K polypeptide . The C-terminal part of the 118K protein contains a consensus sequence for RNA-dependent RNA-polymerases .

The genomic RNA sequence of Southern bean mosaic virus (SBMV) has been determined . The genome contains four ORFs. The largest ORF encodes the two largest proteins translated in cell-free extracts from full-length virion RNA . Segments of the predicted amino acid sequence of this ORF resemble those of known viral RNA-polymerases, ATP-binding proteins and viral genome-linked proteins .

The genome sequence of Pea enation mosaic virus (PEMV) RNA 1 shows strong organisational relationships and sequence similarities to the Beet western yellows virus (BWYV) and PLrV . Sequence analysis reveals five predominant ORFs. The third ORF is characterised by a number of RNA-polymerase motifs and a helicase-like motif typical of RNA-dependent RNA-polymerases . It overlaps (out of frame) the ORF 2 product and is proposed to be expressed by a frameshift fusion of ORF 2 and ORF 3 .

The PLrV sequence shows some similarities to the putative polymerase of SBMV , and more extensive similarities to the corresponding BWYV polypeptide .
Dihydrofolate reductase domain (DHFR_dom)
Type: Domain

Dihydrofolate reductase (DHFR) (

) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, which can be used in
de novo
synthesis both certain amino acids, purines and deoxythymidine phosphate (the precursors of DNA synthesis) , and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood .

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar . The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself .
Ephrin receptor-binding domain (Ephrin_RBD)
Type: Domain

Ephrins are a family of proteins that are ligands of class V (EPH-related) receptor protein-tyrosine kinases. Initially identified as regulators of axon pathfinding and neuronal cell migration, the Eph receptors and their ephrin ligands are now known to have roles in many other cell-cell interactions, including those of vascular endothelial cells and specialised epithelia .

Ephrins are membrane-attached proteins of 205 to 340 residues. Attachment appears to be crucial for their normal function. Type-A ephrins are linked to the membrane via a GPI linkage, while type-B ephrins are type-I membrane proteins.

The globular ephrin receptor-binding domain (ephrin RBD) is a β barrel composed of eight strands arranged in two sheets around a hydrophobic core. Interspersed between β strands are two α helices and one 3(10) helix. The sheets are composed of mixed parallel and antiparallel β strands arranged in a Greek key topology. Like other cell-surface proteins, ephrins contain disulfide bonds to enhance stability. Two buried disulfide bonds are present: one pair holds together β strands C and F, and the other pair anchors two small helices, E and I, at the top of the barrel .
Lipoprotein, OspC-type (Lipoprotein_OspC)
Type: Family

Members of this family are lipoproteins that are probably involved in evasion of the host immune system by Spirochaeta pathogens . Borrelia burgdorferi, the causative agent of Lyme disease, has the potential of producing more than 100 different lipoproteins that could become anchored to the outer membrane . One of these is outer surface protein C (OspC), which acts as an antiphagocytic factor .
DNA-binding protein H-NS-like (Histone_HNS)
Type: Family

The histone-like nucleoid-structuring (H-NS) protein is a DNA-binding protein implicated in transcriptional repression (silencing) as well as in bacterial chromosome organisation . H-NS binds tightly to AT-rich dsDNA, increases its thermal stability and inhibits transcription. It also binds to ssDNA and RNA but with a much lower affinity .
Mercuric transport protein periplasmic component/copper chaperone CopZ (MerP/CopZ)
Type: Family

This entry includes a group of metal binding proteins, including copper chaperone CopZ and mercuric transport protein periplasmic component MerP. They both contain a heavy-metal-associated (HMA) domain.
Orbivirus inner capsid protein VP7 (Orbi_VP7_capsid)
Type: Family

Bluetongue virus is a representative of the Orbivirus genus of the Reoviridae . Orbiviruses infect mammalian hosts through insect vectors, causing economically-important diseases of domesticated animals . They possess a segmented, double-stranded RNA genome within a capsid that comprises four major polypeptides, designated VP2, VP3, VP5 and VP7. On entering a target cell, an outer layer, formed from VP2 and VP5, is removed, leaving an intact core within the cell . The core, which is 70nm across, contains 780 copies of VP7, which together form 260 trimeric 'bristly' capsomeres clothing an inner scaffold constructed from VP3 .

The 3D structure of VP7 reveals two domains, one a β-sandwich, the other a bundle of α-helices, and a short C-terminal arm, which is thought to unite trimers during capsid formation . A concentration of methionine residues at the core of the molecule could provide plasticity, relieving structural mismatches during assembly .

The 3D structure of baculovirus-expressed core protein VP7 of African horse sickness virus 4 (AHSV-4) has been determined to 2.3A resolution . During crystallisation, the two-domain protein is cleaved, leaving only the top domain, in a manner reminiscent of BTV VP7; this suggests that connections between top and bottom domains are relatively weak for these two distinct orbiviruses . The top domains of both BTV and AHSV VP7 are trimeric and structurally very similar. Electron density maps indicate an extra density feature along their molecular 3-fold axes, probably the result of an unidentified ion . The characteristics of the molecular surface indicate the possibility of attachment to the cell via attachment of an Arg-Gly-Asp (RGD) motif in the top domain of VP7 to a cellular integrin for both of these orbiviruses .
Adenosine kinase (Adenokinase)
Type: Family

Adenosine kinase (ADK) phosphorylates adenosine and other related nucleosides . It is exclusive to eukaryotes and is a key enzyme in the purine salvage pathway. ADK catalyses the reaction:

Adenosine + ATP = ADP + AMP

This reaction prevents toxic levels of adenosine building up within the cell. Experiments have been carried out on Gallus gallus (chicken) embryonic neurons to document the toxicity of adenosine, and the associated requirement for ADK .

Adenosine and ATP have been connected with pain, and the control of pain . Associated with this, adenosine has also been shown to have a number of anti-inflammatory activities. Human ADK bears little sequence similarity to other mammalian nucleoside kinases, but does share high similarity with some microbrial ribokinases and fructokinases, suggesting possible evolutionary connections .
Small GTPase (Small_GTPase)
Type: Family

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain . Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity .

Crystallographic analysis of various small G proteins revealed the presence of a 20kDa catalytic domain that is unique for the whole superfamily . The domain is built of five α helices (A1-A5), six β-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound forms allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg2 and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg2 binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base .

The small GTPase superfamily can be divided into at least 8 different families, including:

Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.

Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.

Rab small GTPases. GTP-binding proteins involved in vesicular traffic.

Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.

Ras small GTPases. GTP-binding proteins involved in signalling pathways.

Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).

Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.

Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.
Chloride channel (ClC)
Type: Family

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport . Some members are plasma membrane Cl channels, while others are Cl/H exchangers .

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata , and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl-channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl-channels is that some of the isoforms may function as Cl-channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains . Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N-and C-termini residing in the cytoplasm .

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl-channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia . Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl-channel, lead to several forms of inherited kidney stone disease . These mutations have been demonstrated to reduce or abolish CLC function.
Outer surface lipoprotein, Borrelia (OM_lipoprot_Borrelia)
Type: Family

The ospA and ospB genes encode the major outer membrane proteins of the Lyme disease spirochaete Borrelia burgdorferi . The deduced gene products OspA and OspB, contain 273 and 296 residues respectively . The two Osp proteins show a high degree of sequence similarity, indicating a recent evolutionary event. Molecular analysis and sequence comparison of OspA and OspB with other proteins has revealed similarity to the signal peptides of prokaryotic lipoproteins .
F-box domain (F-box_dom)
Type: Domain

First identified in cyclin-F as a protein-protein interaction motif, the F-box is a conserved domain that is present in numerous proteins with a bipartite structure . Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases . They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats or ANK repeats.
Chemokine interleukin-8-like domain (Chemokine_IL8-like_dom)
Type: Domain

Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related . Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulphide bonds, as shown in the following schematic representation:

+------------------------------------+
| |
xxxxxxxxxxxxxxxxxxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxxxxxxxxxCxxxxx
| |
+-------------------------+

'C': conserved cysteine involved in a disulphide bond.

Chemokines can be sorted into main groups based on the spacing of the two amino-terminal cysteines. In the first group (see

), the two cysteines are separated by a single residue (C-x-C), while in the second group (see

), they are adjacent (C-C).
Trypanosome variant surface glycoprotein, A-type, N-terminal domain (Trypano_VSG_A_N_dom)
Type: Domain

This entry represents the N-terminal of the variant surface glycoproteins from Trypanosome. Proteins containing this domain include a variety of surface proteins such as variant surface glycoprotein and protein PAG1.
Trichovirus movement protein (Trichovirus_mp)
Type: Family

ORF2 of the capilloviruses (trichoviruses) contain a serine peptidase signature which belongs to the MEROPS peptidase family S35 (clan PA(S)). In a number of capilloviruses that have been sequenced to date ORF2 has been identified as the putative movement protein, though it also contains the consensus sequence Gly-Asp-Ser-Gly common to the active site of a number of serine proteases . This family also contains proteins classified as non-peptidase homologues which have either been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity of peptidases in the family. Capilloviruses infect a number of different plant species, and can be detected by the presence of virions in leaf sap.
Translation elongation factor EFTs/EF1B (Transl_elong_EFTs/EF1B)
Type: Family

Translation elongation factors are responsible for two main processes during protein synthesis on the ribosome . EF1A (or EF-Tu) is responsible for the selection and binding of the cognate aminoacyl-tRNA to the A-site (acceptor site) of the ribosome. EF2 (or EF-G) is responsible for the translocation of the peptidyl-tRNA from the A-site to the P-site (peptidyl-tRNA site) of the ribosome, thereby freeing the A-site for the next aminoacyl-tRNA to bind. Elongation factors are responsible for achieving accuracy of translation and both EF1A and EF2 are remarkably conserved throughout evolution.

Elongation factor EF1B (also known as EF-Ts or EF-1beta/gamma/delta) is a nucleotide exchange factor that is required to regenerate EF1A from its inactive form (EF1A-GDP) to its active form (EF1A-GTP). EF1A is then ready to interact with a new aminoacyl-tRNA to begin the cycle again. EF1B is more complex in eukaryotes than in bacteria, and can consist of three subunits: EF1B-alpha (or EF-1beta), EF1B-gamma (or EF-1gamma) and EF1B-beta (or EF-1delta) .

This entry represents EF-Ts (EF1B) proteins found primarily in bacteria, mitochondria and chloroplasts.
Vasopressin receptor (Vasoprsn_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present in high levels in the posterior pituitary. Vasopressin has an essential role in the control of the water content of the body, acting in the kidney to increase water and sodium absorption. In higher concentrations, vasopressin stimulates contraction of vascular smooth muscle, stimulates glycogen breakdown in the liver, induces platelet activation, and evokes release of corticotrophin from the anterior pituitary. Vasopressin and its analogues are used clinically to treat diabetes insipidus. Oxytocin stimulates contraction of uterine smooth muscle, and stimulates milk secretion in response to suckling by inducing contraction of myoepithelial cells in the mammary gland. Clinically, it is used to induce labour and promote lactation.
Peptidase M10, metallopeptidase (Pept_M10_metallopeptidase)
Type: Domain

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

This group of metallopeptidases belong to the MEROPS peptidase family M10 (clan MA(M)).

The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

Sequences having this domain are extracellular metalloproteases, such as collagenase and stromelysin, which degrade the extracellular matrix, are known as matrixins. They are zinc-dependent, calcium-activated proteases synthesised as inactive precursors (zymogens), which are proteolytically cleaved to yield the active enzyme . All matrixins and related proteins possess 2 domains: an N-terminal domain, and a zinc-binding active site domain. The N-terminal domain peptide, cleaved during the activation step, includes a conserved PRCGVPDV octapeptide, known as the cysteine switch, whose Cys residue chelates the active site zinc atom, rendering the enzyme inactive . The active enzyme degrades components of the extracellular matrix, playing a role in the initial steps of tissue remodelling during morphogenesis, wound healing, angiogenesis and tumour invasion .
Chromogranin A/B (Chromogranin_AB)
Type: Family

Chromogranins and secretogranins are acidic proteins present in the secretory granules of endocrine and neuro-endocrine cells . Granins may be precursors of biologically-active peptides, or they may be helper proteins in the packaging of peptide hormones and neuropeptides - their precise role is unclear.

Chromogranins A and B are characterised by an N-terminal motif that includes 2 cysteine residues involved in disulphide bond formation.