SII-SWORD/CoKE huggingface dataset:
Iron dependent repressor (Iron_dep_repressor)
Type: Family

This entry represents a group of iron dependent repressors, including MntR, IdeR and diphtheria toxin repressor.

The diphtheria toxin repressor protein (DTXR) is a member of this group . In Corynebacterium diphtheriae where it has been studied in some detail this protein acts as an iron-binding repressor of diphtheria toxin gene expression and may serve as a global regulator of gene expression. DTXR comprises an N-terminal DNA-binding domain, an interface domain (which contains two metal-binding sites) and a third, very flexible C-terminal domain. The second domain is responsible for dimerization and metal binding. The N terminus may be involved in iron binding and may associate with the Tox operator. Binding of DTXR to Tox operator requires a divalent metal ion such as cobalt, ferric, manganese and nickel whereas zinc shows weak activation .
Transcription elongation factor, GreA/GreB, N-terminal (Tscrpt_elong_fac_GreA/B_N)
Type: Domain

Bacterial proteins GreA and GreB are necessary for efficient RNA polymerase transcription elongation past template-encoded arresting sites. Arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked DNA/RNA/ polymerase ternary complexes. Cleavage of the nascent transcript by cleavage factors, such as GreA or GreB, allows the resumption of elongation from the new 3' terminus . Escherichia coli GreA and GreB are sequence homologues and have homologues in every known bacterial genome . GreA induces cleavage two or three nucleotides behind the terminus and can only prevent the formation of arrested complexes while greB releases longer sequences up to eighteen nucleotides in length and can rescue preexisting arrested complexes. These functional differences correlate with a distinctive structural feature, the distribution of positively charged residues on one face of the N-terminal coiled coil. Remarkably, despite close functional similarity, the prokaryotic Gre factors have no sequence or structural similarity with eukaryotic TFIIS.
Geminivirus AL1 replication-associated protein, central domain (Gemini_AL1_REP_central)
Type: Domain

Geminiviruses are characterised by a genome of circular single-stranded DNA encapsidated in twinned (geminate) quasi-isometric particles, from which the group derives its name . Most geminiviruses can be divided into two subgroups on the basis of host range and/or insect vector: i.e. those that infect dicotyledenous plants and are transmitted by the same whitefly species, and those that infect monocotyledenous plants and are transmitted by different leafhopper vectors. The genomes of the whitefly-transmitted African cassava mosaic virus, Tomato golden mosaic virus (TGMV) and Bean golden mosaic virus (BGMV) possess a bipartite genome. By contrast, only a single DNA component has been identified for the leafhopper-transmitted Maize streak virus (MSV) and Wheat dwarf virus (WDV) . Beet curly top virus (BCTV), and Tobacco yellow dwarf virus belong to a third possible subgroup. Like MSV and WDV, BCTV is transmitted by a specific leafhopper species, yet like the whitefly-transmitted geminiviruses it has a host range confined to dicotyledenous plants.

Sequence comparison of the whitefly-transmitted Squash leaf curl virus (SqLCV) and Tomato yellow leaf curl virus (TYLCV) with the genomic components of TGMV and BGMV reveals a close evolutionary relationship . Amino acid sequence alignments of Potato yellow mosaic virus (PYMV) proteins with those encoded by other geminiviruses show that PYMV is closely related to geminiviruses isolated from the New World, especially in the putative coat protein gene regions . Comparison of MSV DNA-encoded proteins with those of other geminiviruses infecting monocotyledonous plants, including Panicum streak virus and Miscanthus streak virus (MiSV) , reveal high levels of similarity.

This is the central region of the geminivirus rep proteins . It is found C-terminal to

and is thought to be responsible for oligomerisation.
3-hydroxyacyl-CoA dehydrogenase (3-OHacyl-CoA_DH)
Type: Family

3-hydroxyacyl-CoA dehydrogenase (

) (HCDH) is an enzyme involved in fatty acid metabolism and catalyzes the reduction of 3-hydroxyacyl-CoA to 3-oxoacyl-CoA. Most eukaryotic cells have two fatty-acid beta-oxidation systems, one located in mitochondria and the other in peroxisomes. In peroxisomes 3-hydroxyacyl-CoA dehydrogenase forms, with enoyl-CoA hydratase (ECH) and 3,2-trans-enoyl-CoA isomerase (ECI) a multifunctional enzyme where the N-terminal domain bears the hydratase/isomerase activities and the C-terminal domain the dehydrogenase activity. There are two mitochondrial enzymes: one which is monofunctional and the other which is, like its peroxisomal counterpart, multifunctional.

In Escherichia coli (gene fadB) and Pseudomonas fragi (gene faoA) HCDH is part of a multifunctional enzyme which also contains an ECH/ECI domain as well as a 3-hydroxybutyryl-CoA epimerase domain .
Histidinol dehydrogenase, monofunctional (Histidinol_DH_monofunct)
Type: Family

Histidinol dehydrogenase (HDH) catalyses the terminal step in the biosynthesis of histidine in bacteria, fungi, and plants, the four-electron oxidation of L-histidinol to histidine.

In 4-electron dehydrogenases, a single active site catalyses 2 separate oxidation steps: oxidation of the substrate alcohol to an intermediate aldehyde; and oxidation of the aldehyde to the product acid, in this case His . The reaction proceeds via a tightly- or covalently-bound inter-mediate, and requires the presence of 2 NAD molecules . By contrast with most dehydrogenases, the substrate is bound before the NAD coenzyme . A Cys residue has been implicated in the catalytic mechanism of the second oxidative step .

In bacteria HDH is a single chain polypeptide; in fungi it is the C-terminal domain of a multifunctional enzyme which catalyses three different steps of histidine biosynthesis; and in plants it is expressed as nuclear encoded protein precursor which is exported to the chloroplast .

This entry represents histidinol dehydrogenase

.
Homoserine dehydrogenase lacking ACT domain (HDH_short)
Type: Family

This group represents a homoserine dehydrogenase lacking the ACT domain, such as HOM6 from Saccharomyces cerevisiae . It appears to be a naturally occurring feedback resistant homoserine dehydrogenase.
Orsellinic acid/F9775 biosynthesis cluster protein D (OrsD)
Type: Family

This family of proteins includes orsellinic acid/F9775 biosynthesis cluster protein D (orsD) from Emericella nidulans. The orsD gene is part of the cluster that encodes components for the biosynthesis of orsellinic acid, as well as biosynthesis of the cathepsin K inhibitors F9775 A and F9775 B , but the function of orsD is unknown. OrsD contains two segments that are likely to be C2H2 zinc binding domains.
Stonin-2, N-terminal (Stonin2_N)
Type: Domain

Stonin 2 is involved in clathrin mediated endocytosis . It binds to Eps15 by its highly conserved NPF motif. The complex formed has been shown to directly associate with the clathrin adaptor complex AP-2, and to localize to clathrin-coated pits (CCPs) . In addition, stonin2 was recently identified as a specific sorting adaptor for synaptotagmin, and may thus regulate synaptic vesicle recycling .

This entry represents the N-terminal domain of stonin-2. It is found in association with

.
Proteinase, regulatory CLIP domain (CLIP)
Type: Domain

The CLIP domain is a regulatory domain which controls the proteinase action of various proteins of the trypsin family, e.g. easter and pap2. The domain is restricted to the arthropoda and found in varying copy numbers (from one to five in Drosophila proteins). It is always found N-terminal to the chymotrypsin serine protease domain, which belong to MEROPS peptidase family S1A. The CLIP domain remains linked to the protease domain after cleavage of a conserved residue which retains the protein in zymogen form. It is named CLIP because it can be drawn in the shape of a paper clip. It has many disulphide bonds and highly conserved cysteine residues, and so it folds extensively .

The clip domain adopts an α/β mixed fold consisting of two helices and an antiparallel distorted β-sheet made of four strands. The two helices are antiparallel and are almost perpendicular to the β-sheet. Three disulfide bridges (C1-C5, C2-C4, C3-C6) stabilize the β-sheet, C3 being the only cysteine that is not located on a β-strand. The clip domain is located opposite the activation loop and contacts the C-terminal α-helix of the SP domain .
tRNA-queuosine alpha-mannosyltransferase, N-terminal (QTMAN_N)
Type: Domain

This domain is found in tRNA-queuosine alpha-mannosyltransferase (QTMAN, also known as Glycosyltransferase-like domain-containing protein 1 GTDC1) from animals and in uncharacterised bacterial sequences. QTMAN is a glycosyltransferase that specifically catalyses mannosylation of cytoplasmic tRNA(Asp) modified with queuosine at position 34 (queuosine(34)) to form mannosyl-queuosine(34) . Mannosylation of queuosine(34) in tRNA(Asp) is required to slow-down elongation at cognate codons, GAC and GAU, thereby regulating protein translation . This is the N-terminal domain of QTMAN which is about 170 amino acids in length and adopts a Rossmann-fold; these proteins have a glycosyl transferase domain

, at the C-terminal. Two conserved sequence motifs are found within this entry: HENQ and FNS. There is also a single completely conserved residue S that may be functionally important.
DNA (cytosine-5)-methyltransferase 1, replication foci domain (Cytosine_MeTrfase1_RFD)
Type: Domain

This domain is part of a cytosine specific DNA methyltransferase enzyme (DNMT). It functions non-catalytically to target the protein towards replication foci. This allows the DNMT1 protein to methylate the correct residues. This domain targets DMAP1 and HDAC2 to the replication foci during the S phase of mitosis. They are thought to have some importance in conversion of critical histone lysine moieties .

A structure exists for the human cytosine specific DNA methyltransferase replication foci domain .
Domain of unknown function DUF3533 (DUF3533)
Type: Domain

This transmembrane domain is functionally uncharacterised. It is found in bacterial and eukaryotic proteins.
Protein of unknown function DUF2746 (DUF2746)
Type: Family

This entry represents proteins found in tailed bacteriophages and some species of Actinomicetes, including Gene 30 protein from Mycobacterium phage D29. Proteins in this entry are uncharacterised.
Antifungal protein (Antifungal_prot)
Type: Family

Antifungal proteinσ consists of five antiparallel β-strands which are highly twisted creating a β-barrel stabilised by four internal disulphide bridges . A cationic site adjacent to a hydrophobic stretch on the protein surface may constitute a phospholipid binding site . Members of this entry act as inhibitors of growth of human pathogenic molds and yeasts such as PafB and opdH .
Mot1, central domain (Mot1_central_dom)
Type: Domain

This domain is found in Mot1 and related proteins.

The TATA-binding protein (TBP) is a major target for transcriptional regulation. Mot1, a Swi2/Snf2-related ATPase, dissociates TBP from DNA in an ATP dependent process . The N-terminal domain of Mot1 has been shown to bind TBP, NC2 and DNA. Its ATPase domain is at the C terminus .
Serine/threonine-protein kinase Atg1-like, tMIT domain (Atg1-like_tMIT)
Type: Domain

This the Atg13-binding region of Atg1 which comprises two tandem MIT (microtubule interacting and transport) domains, named tMIT .

Members of this entry are Serine/threonine-protein kinases, including Atg1 from yeasts, Unc-51 from C. elegans and Ulk1-2 from humans.

Atg1 is required for vesicle formation in autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway .

Ulk1-2 are involved in autophagy in response to starvation . Ulk1 and Ulk2 regulate filopodia extension and branching of sensory axons. They are important for axon growth, playing an essential role in neurite extension of cerebellar granule cells .

Unc-51 is important for axonal elongation and axonal guidance . It is required for either the maintenance of axons (membrane turnover) or for an unknown neuronal function. C elegans worms lacking Unc-51 exhibit various abnormalities in axonal elongation and axonal structures. Unc-51 could also help control cell size along with Bec-1, as mutations in their corresponding genes results in a reduction in small body size without affecting cell number . Unc-51 is also a component of the Unc-51/Atg-13 complex that is probably recruited by lgg-1 to preautophagosomes and is required for autophagosome formation .
Protein SCAI (SCAI)
Type: Family

SCAI is a transcriptional cofactor and tumour suppressor that suppresses MKL1-induced SRF transcriptional activity. It may function in the RHOA-DIAPH1 signal transduction pathway and regulate cell migration through transcriptional regulation of ITGB1 .
Metallothionein domain, yeast (Metalthion_dom_yeast)
Type: Domain

Metallothioneins are characterised by an abundance of cysteine residues and a lack of generic secondary structure motifs. This protein functions in primary metal storage, transport and detoxification . For the first 40 residues in the protein the polypeptide wraps around the metal by forming two large parallel loops separated by a deep cleft containing the metal cluster . This entry includes copper metallothioneins Cup1-1 and Cup1-2 from budding yeasts. They bind copper and mediate resistance to high concentrations of copper and cadmium .
Ribonuclease Y, N-terminal (RNase_Y_N)
Type: Domain

This domain is found at the N terminus of ribonuclease Y. RNase Y from Bacillus subtilis is the functional equivalent of RNase E from Escherichia coli, even though the two enzymes do not share any sequence similarity. It is involved in the initiation of RNA degradation, interacting with other proteins in a degradosome-like complex . In contrast to B. subtilis, the RNase Y homologue (rny/cvfA) of Staphylococcus aureus is not essential for growth, but plays a major role in virulence gene regulation .

RNase Y has two central KH and HD domains . A coiled-coil domain with the potential to form a leucine zipper has been proposed for residues 30 to 150 at the N terminus .
Beta-Casp domain (Beta_Casp)
Type: Domain

The beta-CASP domain is found C-terminal to the beta-lactamase domain in pre-mRNA 3'-end-processing endonuclease. The active site of this enzyme is located at the interface of these two domains .
Proteinase inhibitor I67, bromein (Prot_inhib_I67_bromein)
Type: Domain

Bromelain inhibitor VI is a double-chain inhibitor consisting of an 11-residue and a 41-residue chain. This protein is the 41-residue heavy chain which is joined to the 11-residue chain by disulphide bonds . The inhibitor acts to inhibit the cysteine proteinase bromelain.
Protein of unknown function DUF2670 (DUF2670)
Type: Family

This bacterial family of proteins has no known function and appears to be restricted to Rickettsiaceae.
Protein of unknown function DUF2671 (DUF2671)
Type: Family

This group of proteins with unknown function is predominantly found in Rickettsiales.
Gcn1, N-terminal (Gcn1_N)
Type: Domain

This domain is found in the N-terminal region of Gcn1 protein, which acts as a translation activator that mediates translational control by regulating Gcn2 kinase activity .
Antimicrobial peptide tachystatin A (Antimicrobial_tachystatin_A)
Type: Family

Tachystatin A contains a cysteine-stabilised triple-stranded β-sheet and shows features common to membrane-interactive peptides. Tachystatin A is thought to have an antimicrobial activity similar to defensins.Tachystatin A is also a chitin-binding peptide .
Protein of unknown function DUF2672 (DUF2672)
Type: Family

This group of proteins with unknown function appears to be restricted to Rickettsiaceae.
Gliding motility-associated protein GldM, C-terminal (Motility-assoc_prot_GldM_C)
Type: Domain

This domain is found in bacteria at the C terminus of the GldM protein. This domain is typically between 169 to 182 amino acids in length and has two completely conserved residues (Y and N) that may be functionally important. GldM, is named for the member from Bacteriodetes Flavobacterium johnsoniae, which is required for a type of rapid gliding motility found in certain members of the Bacteriodetes .
Gliding motility-associated protein GldM, N-terminal (Motility-assoc_prot_GldM_N)
Type: Domain

This domain is found in bacteria at the N terminus of the gliding motility-associated protein, GldM. This domain is typically between 169 to 182 amino acids in length. This domain has two completely conserved residues (Y and N) that may be functionally important. GldM, is named for the member from Flavobacterium johnsoniae UW101 Flavobacterium johnsoniae, which is required for a type of rapid gliding motility found in certain members of the Bacteriodetes .
Protein of unknown function DUF3561 (DUF3561)
Type: Family

This entry represents Inner membrane protein YgbE from Escherichia coli (strain K12) and other proteins predominantly found in Proteobacteria. This family of proteins is functionally uncharacterised. Members of this group of proteins are about 110 amino acids in length.
Non-structural protein ORF8, betacoronavirus (ORF8_betacoronavirus)
Type: Family

This entry includes the ORF8 gene products (also known as NS8, accessory protein 8) from human SARS coronavirus (SARS-CoV), SARS-CoV-2, Bat coronavirus HKU3 and pangolin coronaviruses .

ORF8 is an accessory protein that is not shared by all members of subgenus sarbecovirus. The presence and location of ORF8 in the SARS-CoV-2 genome has led its classification with SARS-CoV . ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts . ORF8 has been suggested to be one of the relevant genes in the study of human adaptation of the virus .

The ORF8 protein is a fast-evolving protein in SARS-related CoVs, with a tendency to recombine and undergo deletions. During the early phases of the SARS (SARS-CoV) epidemic in 2002, human isolates were found to possess a unique continuous ORF8 with 366 nucleotides and a predicted protein with 122 amino acids. During the middle and late phases of the SARS epidemic, two functional ORFs (ORF8a and ORF8b) were emerged; they are predicted to encode two small proteins, 8a with 39 amino acids and 8b with 84 amino acids. Interestingly, SARS-CoV-2 ORF8 has not undergone any significantly measurable deletion events, so its function as a full-length protein might be more important to its pathogenicity . ORF8 plays a role in modulating host immune response which may act by down-regulating major histocompatibility complex class I (MHC-I) . It may inhibit expression of some members of the IFN-stimulated gene (ISG) family including hosts IGF2BP1/ZBP1, MX1 and MX2, and DHX58 . ORF8 also binds to IL17RA receptor, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors, contributing to cytokine storm during COVID-19 infection .
RDM domain, Ret finger protein-like (RDM_domain_RFPL)
Type: Domain

The RFPL defining motif (RDM) is a domain found on RFPL (Ret finger protein like) proteins. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex . The RDM domain is thought to have emerged from a neofunctionalisation event. It is found N-terminal to the SPRY domain (

).
RNA methyltransferase, SpoU/TrmH type, C-terminal domain (rRNA_MeTrfase_SpoU_C)
Type: Domain

This domain is found in bacteria and is about 60 amino acids in length. It is found in association with

. This domain has a conserved LFE sequence motif. Some members of the Pfam family SpoU_methylase,

, carry this very distinctive sequence at their extreme C terminus. The exact function of this domain is not known.
Type II restriction enzyme MunI (Restrct_endonuc_II_MunI)
Type: Family

There are four classes of restriction endonucleases: types I, II,III and IV. All types of enzymes recognise specific short DNA sequences and carry out the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. They differ in their recognition sequence, subunit composition, cleavage position, and cofactor requirements , as summarised below:

Type I enzymes (

) cleave at sites remote from recognition site; require both ATP and S-adenosyl-L-methionine to function; multifunctional protein with both restriction and methylase (

) activities.

Type II enzymes (

) cleave within or at short specific distances from recognition site; most require magnesium; single function (restriction) enzymes independent of methylase.

Type III enzymes (

) cleave at sites a short distance from recognition site; require ATP (but doesn't hydrolyse it); S-adenosyl-L-methionine stimulates reaction but is not required; exists as part of a complex with a modification methylase methylase (

).

Type IV enzymes target methylated DNA.

Type II restriction endonucleases (

) are components of prokaryotic DNA restriction-modification mechanisms that protect the organism against invading foreign DNA. These site-specific deoxyribonucleases catalyse the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. Of the 3000 restriction endonucleases that have been characterised, most are homodimeric or tetrameric enzymes that cleave target DNA at sequence-specific sites close to the recognition site. For homodimeric enzymes, the recognition site is usually a palindromic sequence 4-8 bp in length. Most enzymes require magnesium ions as a cofactor for catalysis. Although they can vary in their mode of recognition, many restriction endonucleases share a similar structural core comprising four β-strands and one α-helix, as well as a similar mechanism of cleavage, suggesting a common ancestral origin . However, there is still considerable diversity amongst restriction endonucleases . The target site recognition process triggers large conformational changes of the enzyme and the target DNA, leading to the activation of the catalytic centres. Like other DNA binding proteins, restriction enzymes are capable of non-specific DNA binding as well, which is the prerequisite for efficient target site location by facilitated diffusion. Non-specific binding usually does not involve interactions with the bases but only with the DNA backbone .

Type II restriction enzyme MunI recognises the palindromic sequence C/AATTG. It makes contact with the DNA via the major groove .