SII-SWORD/CoKE huggingface dataset:
Helicase/SANT-associated domain (HSA_dom)
Type: Domain

The helicase/SANT-associated (HSA) domain is found in eukaryotic proteins, including Helicase SRCAP/p400/DOM , Probable global transcription activator SNF2L2/brahma-homologue and Chromatin modification-related protein EAF1 . While each family has the core sequences that define the HSA domain, they each also have additional sequences that distinguish these families from one another. For example, the sequence HWDY(L/C)EEEM(Q/V) is found in the SRCAP/p400/DOM family, whereas the sequence HQE(Y/F)LNSILQ is found in the SNF2 /brahma family .
HSA was initially predicted to be a DNA-binding domain , but it was later reported to be responsible for the binding to nuclear actin-related proteins (ARPs) and actin . In addition to the SANT and helicase domains, the HSA domain is also found in association with the bromo domain .
RNA helicase, DEAD-box type, Q motif (RNA_helicase_DEAD_Q_motif)
Type: Domain

RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism such as splicing, RNA transport, ribosome biogenesis, translation and RNA decay. They are enzymes that unwind double-stranded RNA molecules in an energy dependent fashion through the hydrolysis of NTP. DEAD-box RNA helicases belong to superfamily 2 (SF2) of helicases. As other SF1 and SF2 members they contain seven conserved motifs which are characteristic of these two superfamilies . DEAD-box is named after the amino acids of motif II or Walker B (Mg2+-binding aspartic acid). Besides these seven motifs, DEAD-box RNA helicases contain a conserved cluster of nine amino-acids (the Q motif) with an invariant glutamine located N-terminally of motif I. An additional highly conserved but isolated aromatic residue is also found upstream of these nine residues . The Q motif is characteristic of and unique to DEAD box family of helicases. It is supposed to control ATP binding and hydrolysis, and therefore it represents a potential mechanism for regulating helicase activity.

Several structural analyses of DEAD-box RNA helicases have been reported . The Q motif is located in close proximity to motif I. The conserved glutamine and aromatic residues interact with the ADP molecule.

Some proteins known to contain a Q motif:

Eukaryotic initiation factor 4A (eIF4A). An ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and required for mRNA binding to ribosome.

Various eukaryotic helicases involved in ribosome biogenesis (DBP3, DRS1, SPB4, MAK5, DBP6, DBP7, DBP9, DBP10).

Eukaryotic DEAD-box proteins involved in pre-mRNA splicing (Prp5p, Prp28p and Sub2p).

DEAD-box proteins required for mitochondrial genome expression (MSS116 and MRH4).

Fungi ATP-dependent RNA helicase DHH1. It is required for decapping and turnover of mRNA.

Fungi ATP-dependent RNA helicase DBP5. It is involved in nucleo-cytoplasmic transport of poly(A) RNA.

Bacterial ATP-dependent RNA helicase rhlB. It is involved in the RNA degradosome, a multi-enzyme complex important in RNA processing and messenger RNA degradation.

Bacterial cold-shock DEAD box protein A.

This entry represents a region stretching from the conserved aromatic residue to one amino acid after the glutamine of the Q motif.
Helicase, superfamily 3, DNA virus (Helicase_SF3_DNA-vir)
Type: Domain

Helicases have been classified in 5 superfamilies (SF1-SF5). All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop) and Walker B (Mg2+-binding aspartic acid) motifs. Superfamily 3 consists of helicases encoded mainly by small DNA viruses and some large nucleocytoplasmic DNA viruses . Small viruses are very dependent on the host-cell machinery to replicate. SF3 helicase in small viruses is associated with an origin-binding domain. By pairing a domain that recognises the ori with a helicase, the virus can bypass the host-cell-based regulation pathway and initiate its own replication. The protein binds to the viral ori leading to origin unwinding. Cellular replication proteins are then recruited to the ori and the viral DNA is replicated.

In SF3 helicases the Walker A and Walker B motifs are separated by spacers of rather uniform, and relatively short, length. In addition to the A and B motifs this family is characterised by a third motif (C) which resides between the B motif and the C terminus of the conserved region. This motif consists of an Asn residue preceded by a run of hydrophobic residues .

Several structures of SF3 helicases have been solved . They all possess the same core α/β fold, consisting of a five-stranded parallel β-sheet flanked on both sides by several α-helices. In contrast to SF1 and SF2 helicases, which have RecA-like core folds, the strand connectivity within the α/β core domain is that of AAA+ proteins . The SF3 helicase proteins assemble into a hexameric ring.

Some proteins known to contain an SF3 helicase domain are listed below:

Polyomavirus large T antigen. It initiates DNA unwinding and replication via interactions with the viral origin of replication.

Papillomavirus E1 protein. An ATP-dependent DNA helicase required for initiation of viral DNA replication.

Parvovirus Rep/NS1 protein, which is also required for the initiation of viral replication.

Poxviridae and other large DNA viruses D5 protein.

Bacteriophage DNA primase/helicase protein.

Bacterial prophage DNA primase/helicase protein.

The entry represents the core α/β fold of the SF3 helicase domain found predominantly in DNA viruses.
UvrD-like helicase, ATP-binding domain (UvrD-like_ATP-bd)
Type: Domain

Helicases have been classified in 5 superfamilies (SF1-SF5). All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop) and Walker B (Mg2+-binding aspartic acid) motifs. For the two largest groups, commonly referred to as SF1 and SF2, a total of seven characteristic motifs have been identified which are distributed over two structural domains, an N-terminal ATP-binding domain and a C-terminal domain. UvrD-like DNA helicases belong to SF1, but they differ from classical SF1/SF2 by a large insertion in each domain. UvrD-like DNA helicases unwind DNA with a 3'-5' polarity .

Crystal structures of several uvrD-like DNA helicases have been solved . They are monomeric enzymes consisting of two domains with a common α-β RecA-like core. The ATP-binding site is situated in a cleft between the N terminus of the ATP-binding domain and the beginning of the C-terminal domain. The enzyme crystallizes in two different conformations (open and closed). The conformational difference between the two forms comprises a large rotation of the end of the C-terminal domain by approximately 130 degrees. This "domain swiveling" was proposed to be an important aspect of the mechanism of the enzyme .

Some proteins that belong to the UvrD-like DNA helicase family are listed below:

Bacterial UvrD helicase. It is involved in the post-incision events of nucleotide excision repair and methyl-directed mismatch repair. It unwinds DNA duplexes with 3'-5' polarity with respect to the bound strand and initiates unwinding most effectively when a single-stranded region is present.

Gram-positive bacterial pcrA helicase, an essential enzyme involved in DNA repair and rolling circle replication. The Staphylococcus aureus pcrA helicase has both 5'-3' and 3'-5' helicase activities.

Bacterial rep proteins, a single-stranded DNA-dependent ATPase involved in DNA replication which can initiate unwinding at a nick in the DNA. It binds to the single-stranded DNA and acts in a progressive fashion along the DNA in the 3' to 5' direction.

Bacterial helicase IV (helD gene product). It catalyzes the unwinding of duplex DNA in the 3'-5' direction.

Bacterial recB protein. RecBCD is a multi-functional enzyme complex that processes DNA ends resulting from a double-strand break. RecB is a helicase with a 3'-5' directionality.

Fungal srs2 proteins, an ATP-dependent DNA helicase involved in DNA repair. The polarity of the helicase activity was determined to be 3'-5'.

This domain is also found bacterial helicase-nuclease complex AddAB, both in subunit AddA and AddB. The AddA subunit is responsable for the helicase activity. AddB also harbors a putative ATP-binding domain which does not play a role as a secondary DNA motor, but that it may instead facilitate the recognition of the recombination hotspot sequences .

This entry represents the ATP-binding domain found in AddA, AddB and UvrD-like helicases.
UvrD-like DNA helicase, C-terminal (DNA_helicase_UvrD-like_C)
Type: Domain

Helicases have been classified in 5 superfamilies (SF1-SF5) . All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop), and Walker B (Mg2+-binding aspartic acid) motifs . For the two largest groups, commonly referred to as SF1 and SF2, a total of seven characteristic motifs have been identified which are distributed over two structural domains, an N-terminal ATP-binding domain and a C-terminal domain.

This entry represents the C-terminal domain.

UvrD-like DNA helicases belong to SF1, but they differ from classical SF1/SF2 by a large insertion in each domain. UvrD-like DNA helicases unwind DNA with a 3'-5' polarity .
Crystal structures of several uvrD-like DNA helicases have been solved . They are monomeric enzymes consisting of two domains with a common α-β RecA-like core. The ATP-binding site is situated in a cleft between the N terminus of the ATP-binding domain and the beginning of the C-terminal domain. The enzyme crystallizes in two different conformations (open and closed). The conformational difference between the two forms comprises a large rotation of the end of the C-terminal domain by approximately 130 degrees. This "domain swiveling" was proposed to be an important aspect of the mechanism of the enzyme .

Some proteins that belong to the uvrD-like DNA helicase family are listed below:

Bacterial UvrD helicase. It is involved in the post-incision events of nucleotide excision repair and methyl-directed mismatch repair. It unwinds DNA duplexes with 3'-5' polarity with respect to the bound strand and initiates unwinding most effectively when a single-stranded region is present.

Gram-positive bacterial pcrA helicase, an essential enzyme involved in DNA repair and rolling circle replication. The Staphylococcus aureus pcrA helicase has both 5'-3' and 3'-5' helicase activities.

Bacterial rep proteins, a single-stranded DNA-dependent ATPase involved in DNA replication which can initiate unwinding at a nick in the DNA. It binds to the single-stranded DNA and acts in a progressive fashion along the DNA in the 3' to 5' direction.

Bacterial helicase IV (helD gene product). It catalyzes the unwinding of duplex DNA in the 3'-5' direction.

Bacterial recB protein. RecBCD is a multi-functional enzyme complex that processes DNA ends resulting from a double-strand break. RecB is a helicase with a 3'-5' directionality.

Fungal srs2 proteins, an ATP-dependent DNA helicase involved in DNA repair. The polarity of the helicase activity was determined to be 3'-5'.
SecA motor DEAD (SecA_motor_DEAD)
Type: Domain

SecA is a cytoplasmic protein of 800 to 960 amino acid residues. The eubacterial secA protein plays an important role in protein export. It interacts with the secY and secE components of the protein translocation system. It has a central role in coupling the hydrolysis of ATP to the transfer of proteins across the membrane.

SecA is a superfamily 2 (SF2) helicase that adapted to translocate proteins. It contains the characteristic DEAD/DEXH ATPase core structure with the seven SF2 motifs .
Tensin phosphatase, C2 domain (Tensin_C2-dom)
Type: Domain

Tensins constitute an eukaryotic family of lipid phosphatases that are defined by the presence of two adjacent domains: a lipid phosphatase domain and a C2-like domain. The tensin-type C2 domain has a structure similar to the classical C2 domain (see

) that mediates the Ca2+-dependent membrane recruitment of several signalling proteins. However the tensin-type C2 domain lacks two of the three conserved loops that bind Ca2+, and in this respect it is similar to the C2 domains of PKC-type . The tensin-type C2 domain can bind phopholipid membranes in a Ca2+ independent manner . In the tumour suppressor protein PTEN, the best characterised member of the family, the lipid phosphatase domain was shown to specifically dephosphorylate the D3 position of the inositol ring of the lipid second messenger, phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domain contains the signature motif HCXXGXXR present in the active sites of protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, two invariant lysines are found only in the tensin-type phosphatase motif (HCKXGKXR) and are suspected to interact with the phosphate group at position D1 and D5 of the inositol ring .
Mononegavirales RNA-directed RNA polymerase catalytic domain (Mononeg_RNA_pol_cat)
Type: Domain

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 .

This entry represents the catalytic domain RNA-directed RNA polymerase.
Auxin efflux carrier, plant type (Auxin_eff_plant)
Type: Family

This entry is mostly composed of known or predicted PIN proteins from plants, though some homologous prokaryotic proteins are also included. The PIN proteins are components of auxin efflux systems from plants. These carriers are saturable, auxin-specific, and localized to the basal ends of auxin transport-competent cells . Plants typically posses several of these proteins, each displaying a unique tissue-specific expression pattern. They are expressed in almost all plant tissues including vascular tissues and roots, and influence many processes including the establishment of embryonic polarity, plant growth, apical hook formation in seedlings and the photo- and gravitrophic responses. These plant proteins are typically 600-700 amino acyl residues long and exhibit 8-12 transmembrane segments.
Glutaredoxin subgroup (Glutaredoxin_subgr)
Type: Domain

Glutaredoxins , also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system .

Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond . It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH ->GSH reductase ->GSH ->GRX ->protein substrates . By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.

Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.

This entry represents a conserved region including the active site of this enzyme.
UDP-glucose/GDP-mannose dehydrogenase, dimerisation (UDP-Glc/GDP-Man_DH_dimer)
Type: Domain

This entry represents an α helical region that serves as the dimerisation interface for these enzymes .

The UDP-glucose/GDP-mannose dehydrogenases are a small group of enzymes which possesses the ability to catalyse the NAD-dependent 2-fold oxidation of an alcohol to an acid without the release of an aldehyde intermediate .

The enzymes have a wide range of functions. In plants UDP-glucose dehydrogenase,

, is an important enzyme in the synthesis of hemicellulose and pectin , which are the components of newly formed cell walls; while in zebrafish UDP-glucose dehydrogenase is required for cardiac valve formation . In Xanthomonas campestris, a plant pathogen, UDP-glucose dehydrogenase is required for virulence .
UDP-glucose/GDP-mannose dehydrogenase, C-terminal (UDP-Glc/GDP-Man_DH_C)
Type: Domain

This entry represents the C-terminal substrate-binding domain of these enzymes. Structural studies indicate that this domain forms an incomplete dinucleotide binding fold .

The UDP-glucose/GDP-mannose dehydrogenases are a small group of enzymes which possesses the ability to catalyse the NAD-dependent 2-fold oxidation of an alcohol to an acid without the release of an aldehyde intermediate .

The enzymes have a wide range of functions. In plants UDP-glucose dehydrogenase,

, is an important enzyme in the synthesis of hemicellulose and pectin , which are the components of newly formed cell walls; while in zebrafish UDP-glucose dehydrogenase is required for cardiac valve formation . In Xanthomonas campestris, a plant pathogen, UDP-glucose dehydrogenase is required for virulence .
NADH:ubiquinone oxidoreductase, 49kDa subunit, conserved site (NADH_UbQ_OxRdtase_49kDa_CS)
Type: Conserved_site

This entry represents a highly conserved region found towards the N terminus of the 49kDa subunit of NADH:ubiquinone oxidoreductase.
Beta-ketoacyl synthase-like, N-terminal (Ketoacyl_synth_N)
Type: Domain

Beta-ketoacyl-ACP synthase

(KAS) is the enzyme that catalyses the condensation of malonyl-ACP with the growing fatty acid chain. It is found as a component of a number of enzymatic systems, including fatty acid synthetase (FAS), which catalyses the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH; the multi-functional 6-methysalicylic acid synthase (MSAS) from Penicillium patulum , which is involved in the biosynthesis of a polyketide antibiotic; polyketide antibiotic synthase enzyme
systems; Emericella nidulans multifunctional protein Wa, which is involved in the biosynthesis of conidial green pigment; Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulation Nod factor fatty acyl chain; and yeast mitochondrial protein CEM1. The condensation reaction is a two step process, first the acyl component of an activated acyl primer is transferred to a cysteine residue of the enzyme and is then condensed with an activated malonyl donor with the concomitant release of carbon dioxide.

This entry represents the N-terminal domain of beta-ketoacyl-ACP synthases and polyketide synthases.
Beta-ketoacyl synthase, C-terminal (Ketoacyl_synth_C)
Type: Domain

Beta-ketoacyl-ACP synthase

(KAS) is the enzyme that catalyses the condensation of malonyl-ACP with the growing fatty acid chain. It is found as a component of a number of enzymatic systems, including fatty acid synthetase (FAS), which catalyses the
formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH; the multi-functional 6-methysalicylic acid synthase (MSAS) from Penicillium patulum , which is involved in the biosynthesis of a polyketide antibiotic; polyketide antibiotic synthase enzyme
systems; Emericella nidulans multifunctional protein Wa, which is involved in the biosynthesis of conidial green pigment; Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulation Nod factor fatty acyl chain; and yeast mitochondrial protein CEM1. The condensation reaction is a two step process, first the acyl component of an activated acyl primer is transferred to a cysteine residue of the enzyme and is then condensed with an activated malonyl donor with the concomitant release of carbon dioxide.

This entry represents the C-terminal domain of beta-ketoacyl-ACP synthases. The active site is contained in a cleft between N-and C-terminal domains, with residues from both domains contributing to substrate binding and catalysis . It is also found in polyketide synthases such as Non-reducing polyketide synthase nscA, reducing polyketide synthase FUB1, Phenolphthiocerol synthesis polyketide synthase type I Pks15/1 and related enzymes .
Peptidase A24A, prepilin type IV, bacterial (Peptidase_A24A_bac)
Type: Family

Cysteine protease activity is dependent on an active dyad of cysteine and histidine, the order and spacing of these residues varying in the 20 or so known families. Cysteine proteases have been grouped into two clans (CA and CB). Families C1, C2 and C10 are loosely termed papain-like and belong to clan CA; five cysteine proteases belong to clan CB; other families have not been assigned to clans. Nearly half of all cysteine proteases are found exclusively in viruses. The order of catalytic cysteine and histidine residues within the primary structure differs between the families and is an indication of convergent evolution .

Bacteria produce a number of protein precursors that undergo post- translational methylation and proteolysis prior to secretion as active proteins. Type IV prepilin leader peptidases, which belong to the C20 family of cysteine proteases, are enzymes that mediate this type of post- translational modification. Type IV pilin is a protein found on the surface of Pseudomonas aeruginosa, Neisseria gonorrhoeae and other Gram-negative pathogens. Pilin subunits attach the infecting organism to the surface of host epithelial cells. They are synthesised as prepilin subunits, which differ from mature pilin by virtue of containing a 6-8 residue leader peptide consisting of charged amino acids. Mature type IV pilins also contain a methylated N-terminal phenylalanine residue.
Arginase (Arginase)
Type: Family

L-Arginine is converted to nitric oxide and citrulline by the enzyme nitric oxide synthase and by the enzyme arginase as a part of the hepatic urea cycle . Arginase is a manganese metalloenzyme containing a metal-activated hydroxide ion, a critical nucleophile in metalloenzymes that catalyze hydrolysis or hydration reactions. A hydrogen bond formed by the metal-bound hydroxide holds the enzyme in the proper orientation for catalysis however non-metal substrate-binding sites are also implicated in the enzyme mechanism. Regeneration of metal-bound hydroxide ion from a metal-bound water molecule requires proton transfer to bulk solvent mediated by a histidine proton shuttle residue.