SII-SWORD/CoKE huggingface dataset:
Hepatitis C virus, Non-structural 5a protein (HCV_NS5a)
Type: Domain

Although Hepatitis A virus, Hepatitis B virus, and Hepatitis C virus have similar names, because they all cause liver inflammation, these are distinctly different viruses both genetically and clinically. The Hepatitis C virus (HCV) is a small (50-80 nm in diameter), enveloped, single-stranded, positive sense RNA virus. It is member of the family Flaviviridae. There are seven genotypes and a number of subtypes with diverse geographic distributions. The genome of HCV consists of a single open reading frame. At the 5' and 3' ends of the RNA are the UTR regions that are not translated into proteins but are important to translation and replication of the viral RNA. The 5' UTR has a ribosome binding site (IRES - Internal ribosome entry site) that starts the translation of unique polyprotein that is later cut by cellular and viral proteases into 10 active structural and non-structural smaller proteins .

This entry represents Non-structural 5a viral protein (NS5A). This zinc-containing phosphoprotein plays a role in the regulation of HCV RNA replication . Biochemical characterization of the complex formed by the interaction of NS5A-RNA show the importance of zinc in this interaction and confirm the binding of the protein to the viral genome . The NS5a protein is phosphorylated when expressed in mammalian cells.
It is thought to interact with the dsRNA-dependent (interferon inducible) kinase PKR,

. It also modulates TNFRSF21/DR6 signaling pathway for viral propagation .
Pyruvate-flavodoxin oxidoreductase, central domain (Pyrv_flavodox_OxRed_cen)
Type: Homologous_superfamily

This superfamily represents a domain found in prokaryotes. It includes a region of the large protein pyruvate-flavodoxin oxidoreductase and the whole pyruvate ferredoxin oxidoreductase gamma subunit protein. It is not known whether the gamma subunit has a catalytic or regulatory role. Pyruvate oxidoreductase (POR) catalyses the final step in the fermentation of carbohydrates in anaerobic microorganisms . This involves the oxidative decarboxylation of pyruvate with the participation of thiamine followed by the transfer of an acetyl moiety to coenzyme A for the synthesis of acetyl-CoA . The family also includes pyruvate flavodoxin oxidoreductase as encoded by the nifJ gene in cyanobacterium which is required for growth on molecular nitrogen when iron is limited .
Peptidase M12B, propeptide (Peptidase_M12B_N)
Type: Domain

This signature covers the region of the propeptide for members of the MEROPS peptidase family M12B (clan MA(M), adamalysin family). The propeptide contains a sequence motif similar to the "cysteine switch" of the matrixins, which mediate cell-cell or cell-matrix interactions.
Proline dehydrogenase domain (Proline_DH_dom)
Type: Domain

The proline oxidase/dehydrogenase

is responsible for the first step in the conversion of proline to glutamate for use as a carbon and nitrogen source. The enzyme requires FAD as a cofactor, and is induced by proline.
Rotavirus non-structural protein NSP3 (Rotavirus_NSP3)
Type: Family

This family consists of rotaviral non-structural RNA binding protein 34 (NS34 or NSP3). The NSP3 protein has been shown to bind viral RNA. The NSP3 protein consists of 3 conserved functional domains; a basic region which binds ssRNA, a region containing heptapeptide repeats mediating oligomerisation and a leucine zipper motif . NSP3 may play a central role in replication and assembly of genomic RNA structures . Rotaviruses have a dsRNA genome and are a major cause cause of acute gastroenteritis in the young of many species .
Alphaherpesvirus glycoprotein I (Herpes_gI)
Type: Family

This family consists of glycoprotein I from various members of the alphaherpesvirinae. These include Human herpesvirus 1 (HHV-1), Human herpesvirus 3 (HHV-3) and Suid herpesvirus 1 (Pseudorabies virus). Glycoprotein I (gI) is important during natural infection, mutants lacking gI produce smaller lesions at the site of infection and show reduced neuronal spread . gI forms a heterodimeric complex with gE; this complex displays Fc receptor activity (binds to the Fc region of immunoglobulin) . Glycoproteins are also important in the production of virus-neutralizing antibodies and cell mediated immunity . The alphaherpesviridae have a dsDNA genome and have no RNA stage during viral replication.
Transcriptional regulator TACO1-like (Transcrip_reg_TACO1-like)
Type: Family

This is a family of transcriptional regulators. In mammals, TACO1 (

) activates the transcription of mitochondrially-encoded cytochrome c oxidase (COX1). Defects in TACO1 are a cause of Leigh syndrome (LS). LS is a severe neurological disorder characterised by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency . In Pseudomonas aeruginosa, a member of this family, PmpR, is involved in regulation of the quinolone signal (PQS) system and of pyocyanine production. It negatively regulates the quorum-sensing response regulator pqsR of the PQS system by binding to its promoter region .
Ribosomal RNA methyltransferase, FtsJ domain (RNA_MeTrfase_FtsJ_dom)
Type: Domain

This entry represents FtsJ domain, which is found in proteins that methylate RNA, including Ribosomal RNA large subunit methyltransferase E (formerly known as RrmJ or FtsJ). RrmJ is a well conserved heat shock protein with close homologs in prokaryotes, archaea, and eukaryotes. RrmJ is responsible for methylating 23 S rRNA at position U2552 in the aminoacyl (A)1-site of the ribosome . U2552 is one of the five universally conserved A-loop residues and has been shown to be methylated at the ribose 2'-OH group in the majority of organisms investigated so far. This suggests that this modification plays an important role in the A-loop function. RrmJ recognises its methylation target only when the 23 S rRNA is present in 50 S ribosomal subunits. This suggests that the RrmJ-mediated methylation must occur late in the maturation process of the ribosome. This is in contrast to other known 23 S rRNA modifications that occur in earlier maturation steps.

The 1.5 A crystal structure of RrmJ in complex with its cofactor S-adenosylmethionine revealed that RrmJ has a methyltransferase fold. The active site of RrmJ appears to be formed by a catalytic triad consisting of two lysine residues and the negatively charged aspartate residue. Another highly conserved glutamate residue that is present in the active site of RrmJ appears to play only a minor role in the methyltransfer reaction in vivo .
ChsH2, C-terminal OB-fold domain (ChsH2_C)
Type: Domain

This domain is found at the C-terminal end of the probable enoyl-CoA hydratase alpha subunit from Thermomonospora curvata (ChsH2) and similar archaeal and bacterial proteins. ChsH2 is likely to be involved in bile acid degradation. The C-terminal region of this protein is organised into two domains: an N-terminal zinc finger domain with a three-stranded antiparallel β-sheet and an N-terminal α-helix (

), and a C-terminal domain (this entry) with an oligonucleotide/oligosaccharide binding (OB)-fold that consists of a five-stranded β-barrel . OB-folds are frequently found to bind nucleic acids suggesting this domain might bind to DNA or RNA .

This domain is also found at the C terminus of 3-oxo-4,17-pregnadiene-20-carboxyl-CoA hydratase alpha subunit from M. tuberculosis, which is involved in cholesterol side chain degradation . This enzyme catalyses the hydration of 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA) to form 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA), in the modified beta-oxidation pathway for cholesterol side chain degradation .

Other members of this group of proteins are Geobacter metallireducens Benzoylsuccinyl-CoA thiolase subunit BbsA, a component of the BbsAB thiolase complex, which catalyses the thiolytic cleavage of (S)-2-benzoylsuccinyl-CoA to succinyl-CoA and benzoyl-CoA, the final step of anaerobic toluene metabolism , and Methanothermococcus thermolithotrophicus HMGCS, an enzyme complex comprising the thiolase and 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase, that catalyses the second reaction in the mevalonate pathway-the exergonic condensation of acetoacetyl-CoA and acetyl-CoA to HMG-CoA .
Pyruvate flavodoxin/ferredoxin oxidoreductase, pyrimidine binding domain (Pyrv_Fd/Flavodoxin_OxRdtase_N)
Type: Domain

This entry represents the N-terminal region of the pyruvate ferredoxin oxidoreductase, corresponding to the first two structural domains. This region is involved in inter subunit contacts . Pyruvate oxidoreductase (POR) catalyses the final step in the fermentation of carbohydrates in anaerobic microorganisms . This involves the oxidative decarboxylation of pyruvate with the participation of thiamine followed by the transfer of an acetyl moiety to coenzyme A for the synthesis of acetyl-CoA . The family also includes pyruvate flavodoxin oxidoreductase as encoded by the nifJ gene in cyanobacterium which is required for growth on molecular nitrogen when iron is limited .

The PYR domain is found in many key metabolic enzymes which use TPP (also known as thiamine diphosphate) as a cofactor. TPP binds in the cleft formed by a PYR domain and a PP domain. The PYR domain, binds the aminopyrimidine ring of TPP, the PP domain binds the diphosphate residue. A polar interaction between the conserved glutamate of the PYR domain and the N1' of the TPP aminopyrimidine ring is shared by most TPP-dependent enzymes, and participates in the activation of TPP. The PYR and PP domains have a common fold, but do not share strong sequence conservation. The PP domain is not included in this entry. Most TPP-dependent enzymes have the PYR and PP domains on the same subunit although these domains can be alternatively arranged in the primary structure. TPP-dependent enzymes are multisubunit proteins, the smallest catalytic unit being a dimer-of-active sites. For many of these enzymes the active sites lie between PP and PYR domains on different subunits. However, for the homodimeric enzyme Desulfovibrio africanus pyruvate:ferredoxin oxidoreductase (PFOR), each active site lies at the interface of the PYR and PP domains from the same subunit .
Domain of unknown function DUF58 (DUF58)
Type: Domain

This domain is found in a family of prokaryotic proteins that have no known function. Proteins belonging to this family include hypothetical proteins from eubacteria and archaebacteria. Some of these proteins also contain the Von Willebrand factor, type A domain (see

).
2-phospho-L-lactate transferase CofD (CofD)
Type: Family

This entry contains 2-phospho-L-lactate transferase (CofD), phosphoenolpyruvate transferase and related sequences. CofD catalyses the fourth step in the biosynthesis of coenzyme F420, which is the transfer of the 2-phospholactate moiety from lactyl (2) diphospho-(5') guanosine (LPPG) to 7,8-didemethyl-8-hydroxy-5-deazariboflavin (FO) with the formation of the L-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F420-0) and GMP. F420 is a flavin derivative found in methanogens, Mycobacteria, and several other lineages. This enzyme is characterised so far in Methanocaldococcus jannaschii (Methanococcus jannaschii) but appears restricted to F420-containing species and is predicted to carry out the same function in these other species. CofD monomer contains twelve β-strands, seven of them forming a Rossmann fold, and thirteen α-helices .
CBM10/dockerin domain (CBM10/Dockerin_dom)
Type: Domain

Plant cell wall hydrolases generally have a modular structure consisting of a catalytic domain linked to one or more noncatalytic carbohydrate-binding modules (CBMs). The majority of these CBMs interact with cellulose and are thus referred to as cellulose-binding domains or CBDs. CBM10s are small molecules, comprising only ca. 45 residues, that bind to insoluble forms of cellulose. CBM10s contain three tryptophan and two tyrosine residues which are completely conserved. The CBM10 domain is found in xylanases, mannanases and cellulases from aerobic bacteria and anaerobic fungi .

In aerobic bacteria, this domain binds cellulose (or other carbohydrates); but in anaerobic fungi this domain, also known as the dockerin domain, may be responsible for the assembly of a multiprotein cellulase/hemicellulase complex, similar to the cellulosome found in certain anaerobic bacteria .

This domain consists of two antiparallel β-sheets, one with two strands and one with three, with a short α-helix across one face of the three-stranded sheet .
P domain (P_dom)
Type: Domain

In eukaryotes, many essential secreted proteins and peptide hormones are excised from larger precursors by members of a class of calcium-dependent endoproteinases, the prohormone-proprotein convertases (PCs).The P (known as such because it is essential for proteolytic activity), or Homo B, domain of ~150 residues is a distinctive characteristic of members of the proprotein convertase family. The P/Homo B domain appears to be necessary to both fold and maintain the subtilisin-like active catalytic module and to regulate its specialized features of calcium and more acidic pH dependence .

The core of the P/Homo B domain consists of a jelly roll-like fold with eight β-strands. Nonbonded interactions between the catalytic and P/Homo B domains provide additional structural stabilization of the catalytic domains, which alone appear to be thermodynamically unstable .

Most of the PC family members contained the cognate integrin binding RGD sequence within the middle of the P domain , which may be required for intracellular compartmentalization and maintenance of enzyme stability within the ER. The integrity of the RGD sequence of proprotein convertase PC1 is critical for its zymogen and C-terminal processing and for its cellular trafficking . The carboxy-terminal tail provides uniqueness to each PC family member being the least conserved region of all convertases .
Pentatricopeptide repeat (PPR_rpt)
Type: Repeat

This entry represents the PPR repeat.

Pentatricopeptide repeat (PPR) proteins are characterised by tandem repeats of a degenerate 35 amino acid motif . PPR proteins are sequence-specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism . They can bind a diversity of sequences that confers the variability in its functions . Most have roles in mitochondria or plastids . PPR repeats were discovered while screening Arabidopsis proteins for those predicted to be targeted to mitochondria or chloroplast . Some of these proteins have been shown to play a role in post-transcriptional processes within organelles . Plant genomes have between one hundred to five hundred PPR genes per genome whereas non-plant genomes encode two to six PPR proteins.

The plant PPR protein family has been divided in two subfamilies on the basis of their motif content and organisation .

The crystal structure of maize chloroplast PPR10 has been reported. The nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms a homodimer and exhibits considerable conformational changes upon binding to its ssRNA target, with six nucleotides being specifically recognised by six corresponding PPR10 repeats .
[2Fe-2S]-binding (2Fe-2S-bd)
Type: Domain

The [2Fe-2S] binding domain is found in a range of enzymes including dehydrogenases, oxidases and oxidoreductases.

The aldehyde oxido-reductase (Mop) from the sulphate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas is a homodimer of 907 amino acid residues subunits and is a member of the xanthine oxidase family. The protein contains a molybdopterin cofactor (Mo-co) and two different [2Fe-2S] centres. It is folded into four domains of which the first two bind the iron sulphur centres and the last two are involved in Mo-co binding. Mo-co is a molybdenum molybdopterin cytosine dinucleotide. Molybdopterin forms a tricyclic system with the pterin bicycle annealed to a pyran ring. The molybdopterin dinucleotide is deeply buried in the protein. The cis-dithiolene group of the pyran ring binds the molybdenum, which is coordinated by three more (oxygen) ligands .
Carbohydrate-binding WSC (WSC_carb-bd)
Type: Domain

The WSC domain is a putative carbohydrate binding domain. The domain contains up to eight conserved cysteine residues that may be involved in disulphide bridges . The Trichoderma harzianum beta-1,3 exoglucanase contains two copies of the WSC domain, while the yeast SLG1 protein contains only one. This domain folds as a sandwich of five antiparallel β-sheet and a single α-helix, with similarity with the hepatocyte growth factor (

, .
Macroglobulin domain (MG2)
Type: Domain

The proteinase-binding alpha-macroglobulins (A2M) are large glycoproteins found in the plasma of vertebrates, in the hemolymph of some invertebrates and in reptilian and avian egg white. A2M-like proteins are able to inhibit all four classes of proteinases by a 'trapping' mechanism. They have a peptide stretch, called the 'bait region', which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein, thus trapping the proteinase. The entrapped enzyme remains active against low molecular weight substrates, whilst its activity toward larger substrates is greatly reduced, due to steric hindrance. Following cleavage in the bait region, a thiol ester bond, formed between the side chains of a cysteine and a glutamine, is cleaved and mediates the covalent binding of the A2M-like protein to the proteinase.

This entry represents the MG2 (macroglobulin) domain of alpha-2-macroglobulin and related thioester-containing proteins (TEPs [

,

. A2M-like proteins have been identified in pathogenic invasive bacteria and species that colonize higher eukaryotes. This domain is found in eukaryotic and bacterial proteins. In human A2Ms, this domain is termed macroglobulin-like (MG) domain 2 and in Salmonella enterica ser A2Ms, this is domain 4 .
Adenylyl-sulfate kinase (APS_kinase)
Type: Family

Adenylylsulphate kinase (

) catalyses the phosphorylation of adenylylsulphate to 3'-phosphoadenylylsulphate. It is often found as a fusion protein with sulphate adenylyltransferase. Both enzymes are required for PAPS (phosphoadenosine-phosphosulphate) synthesis from inorganic sulphate .
Zinc finger, MYND-type (Znf_MYND)
Type: Domain

This entry represents MYND-type zinc finger domains. The MYND domain (myeloid, Nervy, and DEAF-1) is present in a large group of proteins that includes RP-8 (PDCD2), Nervy, and predicted proteins from Drosophila, mammals, Caenorhabditis elegans, yeast, and plants . The MYND domain consists of a cluster of cysteine and histidine residues, arranged with an invariant spacing to form a potential zinc-binding motif . Mutating conserved cysteine residues in the DEAF-1 MYND domain does not abolish DNA binding, which suggests that the MYND domain might be involved in protein-protein interactions . Indeed, the MYND domain of ETO/MTG8 interacts directly with the N-CoR and SMRT co-repressors . Aberrant recruitment of co-repressor complexes and inappropriate transcriptional repression is believed to be a general mechanism of leukaemogenesis caused by the t(8;21) translocations that fuse ETO with the acute myelogenous leukemia 1 (AML1) protein. ETO has been shown to be a co-repressor recruited by the promyelocytic leukaemia zinc finger (PLZF) protein . A divergent MYND domain present in the adenovirus E1A binding protein BS69 was also shown to interact with N-CoR and mediate transcriptional repression . The current evidence suggests that the MYND motif in mammalian proteins constitutes a protein-protein interaction domain that functions as a co-repressor-recruiting interface.

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Paramecium surface antigen (Paramecium_SA)
Type: Repeat

The G surface protein of Paramecium primaurelia has important internal homologies and a periodic structure, which could be dictated in part by the rigid scaffolding of cysteine residues. The predicted secondary structure shows a quasi absence of α-helix and an abundance of β-pleated sheets and random coils. The monotony of the amino acid sequence is in favour of a structural role for the protein . This structure is based on the presence of 37 periods of about 75 residues, each period containing eight cysteine residues . Homologies with other proteins are limited to surface antigens of trypanosomes.
Herpesvirus glycoprotein D/GG/GX domain (Herpes_glycop_dom)
Type: Domain

Herpesviruses are dsDNA viruses with no RNA stage. This entry represents a conserved domain found in several Herpes viruses glycoproteins, including:

Glycoprotein-D (gD or gIV), which is common to Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2), as well as Equid herpesvirus 1, Bovine herpesvirus 1 and Meleagrid herpesvirus 1 (MeHV-1). Glycoprotein-D has been found on the viral envelope and the plasma membrane of infected cells. gD immunisation can produce an immune response to bovine herpes virus (BHV-1). This response is stronger than that of the other major glycoproteins gB (gI) and gC (gIII) in BHV-1 .

Glycoprotein G (gG), which is one of the seven external glycoproteins of Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2) . In the HHV-2 virus-infected cell, gG-2 is cleaved into a secreted amino-terminal portion (sgG-2) and a carboxy-terminal portion. The latter protein is further O-glycosylated, generating the cell membrane-associated mature gG-2 (mgG-2). The mgG-2 protein has widely been used as a prototype antigen for detection of type-specific antibodies against HHV-2 .

Glycoprotein GX (gX), which was initially identified in Suid herpesvirus 1 (Pseudorabies virus).
MotA/TolQ/ExbB proton channel (MotA_ExbB_proton_chnl)
Type: Domain

This entry represents transmembrane helices of integral membrane proteins that appear to be involved in translocation of proteins or ions across a membrane. These proteins are probably proton channels. MotA is an essential component of the flagellar motor that uses a proton gradient to generate rotational motion in the flagellar . ExbB is part of the TonB-dependent transduction complex. The TonB complex uses the proton gradient across the inner bacterial membrane to transport large molecules across the outer bacterial membrane.
Domain of unknown function DUF38/FTH, Caenorhabditis species (DUF38/FTH_CAE_spp)
Type: Domain

This domain with no known function is presumed to be a protein-protein interaction module specific to proteins from several Caenorhabditis species. It is named FTH after FOG-2 homology domain . The domain is found associated with, and C-terminal to, the cyclin-like F-box

.