SII-SWORD/CoKE huggingface dataset:
Sirohaem synthase, dimerisation domain (Sirohaem_synthase_dimer_dom)
Type: Domain

Bacterial sulphur metabolism depends on the iron-containing porphinoid sirohaem. CysG is a multi-functional enzyme with S-adenosyl-L-methionine (SAM)-dependent bismethyltransferase, dehydrogenase and ferrochelatase activities. CysG synthesizes sirohaem from uroporphyrinogen III via reactions which encompass two branchpoint intermediates in tetrapyrrole biosynthesis, diverting flux first from protoporphyrin IX biosynthesis and then from cobalamin (vitamin B12) biosynthesis. CysG is a dimer. Its dimerisation region is 74 residues long, and acts to hold the two structurally similar protomers held together asymmetrically through a number of salt-bridges across complementary residues within the dimerisation region . CysG dimerisation produces a series of active sites, accounting for CysG's multi-functionality, catalysing four diverse reactions:

Two SAM-dependent methylations

NAD+-dependent tetrapyrrole dehydrogenation

Metal chelation
Peroxiredoxin, C-terminal (Peroxiredoxin_C)
Type: Domain

This entry represents the C-terminal domain of 1-Cys peroxiredoxin, a member of the peroxiredoxin superfamily which protect cells against membrane oxidation through glutathione (GSH)-dependent reduction of phospholipid hydroperoxides to corresponding alcohols . The C-terminal domain is crucial for providing the extra cysteine necessary for dimerisation of the whole molecule. Loss of the enzyme's peroxidase activity is associated with oxidation of the catalytic cysteine found upstream of this domain. Glutathionylation, presumably through its disruption of protein structure, facilitates access for GSH, resulting in spontaneous reduction of the mixed disulphide to the sulphydryl and consequent activation of the enzyme . The domain is associated with

, which carries the catalytic cysteine.
Dihydroorotate dehydrogenase, electron transfer subunit, iron-sulphur cluster binding domain (Dihydroorotate_DH_Fe-S-bd)
Type: Domain

Lactococcus lactis is one of the few organisms with two dihydroorotate dehydrogenases (DHODs) A and B . The B enzyme is typical of DHODs in Gram-positive bacteria that use NAD+ as the second substrate. DHODB is a heterotetramer composed of a central homodimer of PyrDB subunits resembling the DHODA structure and two PyrK subunits along with three different cofactors: FMN, FAD, and a [2Fe-2S] cluster. The [2Fe-2S] iron-sulphur cluster binds to this C-terminal domain of the PyrK subunit, which is at the interface between the flavin and NAD binding domains and contains three β-strands. The four cysteine residues at the N-terminal part of this domain are the ones that bind, in pairs, to the iron-sulphur cluster. The conformation of the whole molecule means that the iron-sulphur cluster is localized in a well-ordered part of this domain close to the FAD binding site . The FAD and NAD binding domains are

and

respectively.
Transcription factor TFIIIC, triple barrel domain (TFIIIC_triple_barrel)
Type: Domain

This conserved domain is found in a family of proteins that function as subunits of transcription factor IIIC (TFIIIC) . TFIIIC in yeast and humans is required for transcription of tRNA and 5 S RNA genes by RNA polymerase III. The yeast proteins in this entry are fused to phosphoglycerate mutase domain.
Interleukin-12 beta, central domain (IL-12_beta_cen-dom)
Type: Domain

This entry represents the central domain (domain 2) of the beta subunit (also known as subunit p40) interleukin-12 (IL-12). This domain is largely β-stranded with a fibronectin III-like structure. IL-12 is produced on stimulation by macrophage-engulfed micro-organisms and other stimuli, when it dimerises with IL-12 subunit alpha (subunit p35) to form a heterodimer which then binds to receptors on natural killer cells to activate them to destroy the micro-organisms . This domain contains two disulphide bridges, one of which serves to bind the beta subunit to the alpha subunit, and the other to hold the β strands within the domain together. The cupped shape of the alpha subunit binding interface matches the elbow-like bend between domains 2 and 3 in the beta subunit . Domain 3 also has a fibronectin iii-like structure.
V(D)J recombination-activating protein 1, Zinc finger (RAG1_Znf)
Type: Domain

The development of B and T cells depends on the rearrangement of variable (V), diversity (D), and joining (J) gene segments to produce mature Ig and T cell receptor coding regions. This rearrangement process, known as V(D)J recombination is initiated by the complex, multi-domain proteins RAG1 and RAG2. The RAG proteins catalyze DNA cleavage in the first phase of the reaction using a recombination signal sequence (RSS) that flanks V, D and J segments .

RAG1 contains a zinc-binding dimerization domain immediately N-terminal to the catalytic core region, which in turn contains a putative DNA-binding domain at its N terminus. The dimerization domain consists of a zinc C3HC4 RING finger and a C2H2 zinc RAG1-type finger.

The C2H2 RAG1-type zinc finger contains the hallmarks of a classical zinc finger structure with a two stranded β-sheet and an α-helix .
Argonaute hook domain (Argonaute_hook_dom)
Type: Domain

This entry represents a region called the argonaute hook . It has been shown to bind to the Piwi domain (

) of argnonaute proteins.
RAM signalling pathway, SOG2 (RAM_signalling_pathway_SOG2)
Type: Family

The RAM signalling pathway regulates Ace2p transcription factor activity and cellular morphogenesis in Saccharomyces cerevisiae (Baker's yeast), and is thought to be conserved amongst eukaryotes .
Nuclear pore RNA shuttling protein Mtr2 (Nucl_pore_RNA_shuttling_Mtr2)
Type: Family

Mtr2 is a monomeric, dual-action, RNA-shuttle protein found in yeasts. Transport across the nuclear-cytoplasmic membrane is via the macro-molecular membrane-spanning nuclear pore complex, NPC. The pore is lined by a subset of NPC members called nucleoporins that present FG (Phe-Gly) receptors, characteristically GLFG and FXFG motifs, for shuttling RNAs and proteins. RNA cargo is bound to soluble transport proteins (nuclear export factors) such as Mex67 in yeasts, and TAP in metazoa, which pass along the pore by binding to successive FG receptors. Mtr2 when bound to Mex67 maximises this FG-binding. Mtr2 also acts independently of Mex67 in transporting the large ribosomal RNA subunit through the pore .
Clp ATPase, C-terminal (Clp_ATPase_C)
Type: Domain

Most Clp ATPases form complexes with peptidase subunits and are involved in protein degradation, though some, such as ClpB, do not associate with peptidases and are involved in protein disaggregation . This entry represents the C-terminal domain of Clp ATPases, often referred to as the D2-small domain, which forms a mixed α-β structure. Compared with the adjacent AAA D1-small domain (

) it lacks the long coiled-coil insertion, and instead of helix C4 contains a β-strand (e3) that is part of a three stranded β-pleated sheet. In Thermophilus the whole protein forms a hexamer with the D1-small and D2-small domains located on the outside of the hexamer, with the long coiled-coil being exposed on the surface. The D2-small domain is essential for oligomerisation, forming a tight interface with the D2-large domain of a neighbouring subunit, thereby providing enough binding energy to stabilise the functional assembly .
Bifunctional glucose-6-phosphate/mannose-6-phosphate isomerase, C-terminal (Glu6P/Mann6P_isomerase_C)
Type: Domain

Phosphoglucose isomerase (PGI) catalyses the interconversion of phosphoglucose and phosphofructose, and is a component of many sugar metabolic pathways. In some archaea and bacteria PGI activity occurs via a bifunctional enzyme that also exhibits phosphomannose isomerase (PMI) activity. Though not closely related to eukaryotic PGIs, the bifunctional enzyme is similar enough that the sequence includes the cluster of threonines and serines that forms the sugar phosphate-binding site in conventional PGI.

The bifunctional PGI/PMI enzyme contains two SIS (Sugar ISomerase) domains. This entry represents the C-terminal SIS domain, which contains many of the active catalytic site residues. The enzyme is thought to use the same catalytic mechanisms for both glucose ring-opening and isomerisation for the interconversion of glucose 6-phosphate to fructose 6-phosphate .
Lipoate protein ligase, C-terminal (Lipoate_protein_ligase_C)
Type: Domain

This is the C-terminal domain of a bacterial lipoate protein ligase . There is no conservation between this C terminus and that of vertebrate lipoate protein ligase C-termini, but both are associated with

, further upstream. This C-terminal domain is more stable than

and the hypothesis is that the C-terminal domain has a role in recognising the lipoyl domain and/or transferring the lipoyl group onto it from the lipoyl-AMP intermediate. C-terminal fragments of length 172 to 193 amino acid residues are observed in the eubacterial enzymes whereas in their archaeal counterparts the C-terminal segment is significantly smaller, ranging in size from 87 to 107 amino acid residues.
Cyclo-malto-dextrinase, C-terminal (Cyclo-malto-dextrinase_C)
Type: Domain

This domain is at the very C terminus of cyclo-malto-dextrinase proteins and consists of 8 β strands, is largely globular and appears to help stabilise the active sites created by upstream domains,

, and

. Cyclo-malto-dextrinases hydrolyse cyclodextrans to maltose and glucose and catalyse trans-glycosylation of oligosaccharides to the C3-, C4- or C6-hydroxyl groups of various acceptor sugar molecules.
Bacteriocin, class IIb, lactacin-related (Bacteriocin_IIb_lactacin-rel)
Type: Family

Bacteriocins are proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely related strains. The producer bacteria are protected from the effects of their own bacteriocins by production of a specific immunity protein which is co-transcribed with the genes encoding the bacteriocins, e.g.

. The bacteriocins are structurally more specific than their immunity-protein counterparts. Typically, production of the bacteriocin gene is from within an operon carrying up to 6 genes including a typical two-component regulatory system (R and H), a small peptide pheromone (C), and a dedicated ABC transporter (A and -B) as well as an immunity protein . The ABC transporter is thought to recognise the N termini of both the pheromone and the bacteriocins and to transport these peptides across the cytoplasmic membrane, concurrent with cleavage at the conserved double-glycine motif. Cleaved extracellular C can then bind to the sensor kinase, H, resulting in activation of R and up-regulation of the entire gene cluster via binding to consensus sequences within each promoter . It seems likely that the whole regulon is carried on a transmissible plasmid which is passed between closely related Firmicute species since many clinical isolates from different Firmicutes can produce at least two bacteriocins, and the same bacteriocins can be produced by different species.

The proteins in this entry include amylovorin-L, lactacin-F subunit LafA and subunit LafX all of them class IIb two-peptide bacteriocins.
FIST, C-domain (FIST_C)
Type: Domain

This entry represents a novel sensory domain, designated FIST_C (short for F-box and intracellular signal transduction, C-terminal), which is present in signal transduction proteins from bacteria, archaea and eukaryotes. The chromosomal proximity of FIST-encoding genes to those coding for proteins involved in amino acid metabolism and transport suggest that FIST domains bind small ligands, such as amino acids .
Exosome complex component CSL4, C-terminal (EXOSC1_C)
Type: Domain

Exosome is a complex of 3' --> 5' exoribonucleases that play a major role in diverse RNA processing and degradation pathways. The eukaryotic exosome complex contains 9 proteins. Six RNase PH domain containing proteins (Rrp41, Rrp42, Rrp43, Rrp45, Rrp46, and Mtr3) form a catalytic ring, three RNA binding domain containing proteins (Rrp4,Rrp40, and Csl4) bind on top of the ring .

This entry represents the C-terminal domain of the exosome complex component CSL4 (also known as EXOSC1). CSL4 does not have exonuclease activity, but are required for the 3'-processing of the 7S pre-RNA to the mature 5.8S rRNA and for mRNA decay .
FMR1-interacting protein 1, conserved domain (NUFIP1_cons_dom)
Type: Domain

FMR1-interacting protein 1 (Nufip1) has been implicated in the assembly of the large subunit of the ribosome and in telomere maintenance . It is known to bind RNA and is phosphorylated upon DNA damage . This entry represents a conserved domain found within Nufip1. Some proteins containing this region also contain a CCCH zinc finger.
Sorting nexin protein, WASP-binding domain (Sorting_nexin_WASP-bd-dom)
Type: Domain

The C-terminal region of the Sorting nexin group of proteins appears to carry a BAR-like (Bin/amphiphysin/Rvs) domain. This domain is very diverse and the similarities with other BAR domains are few. In the Sorting nexins it is associated with

, and in combination with PX appears to be necessary to bind WASP along with p85 to form a multimeric signalling complex .
MENTAL domain (MENTAL)
Type: Domain

The following proteins share a conserved region called the MENTAL (MLN64 N-terminal) domain, composed of four transmembrane helices with three short intervening loops :

Animal MLN64 (metastatic lymph node 64), a late endosomal membrane protein containing a carboxyl-terminal cholesterol binding START domain (

). It is probably involved in intracellular cholesterol transport.

Mammalian MENTHO (MLN64 N-terminal domain homologue), a late endosomal protein containing only the MENTAL domain. It is probably involved in cellular cholesterol homoeostasis.

The ~170-amino acid MENTAL domain mediates MLN64 and MENTHO homo- and hetero- interactions, targets both proteins to late endosomes and binds cholesterol. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s) through the START domain.
Valyl-tRNA synthetase, tRNA-binding arm (Val-tRNA_synth_tRNA-bd)
Type: Domain

This entry represents the C-terminal domain of Valyl-tRNA synthetase, which consists of two helices in a long α-hairpin .

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .
Peptidase S46 (Pep_S46)
Type: Family

Dipeptidyl aminopeptidase BII from Pseudoxanthomonas mexicana is a serine protease classified into clan PA, family S46. It is able to cleave a variety of dipeptides from the amino-terminus of substrate peptides . Another characterised member of the S46 family of dipeptidyl-peptidases from bacteria is dipeptidyl-peptidase 7 (DPP-7) from Porphyromonas gingivalis. It may serve nutritional functions by providing dipeptides to this asaccharolytic bacterium .
Peptidase M30, hyicolysin (Peptidase_M30_hyicolysin)
Type: Family

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 family contains metallopeptidases belonging to MEROPS peptidase family M30 (hyicolysin family, clan MA). Hyicolysin (ShpI) is a neutral metalloprotease from Staphylococcus hyicus It has a zinc ion which is liganded by two histidine and one glutamate residue.
Peptidase S68, pidd (Peptidase_S68_pidd)
Type: Family

This entry contains serine peptidases belonging to MEROPS peptidase family S68 (PIDD auto-processing protein, clan S-). These proteins are known as Pidd (short for p53-induced protein with a death domain) proteins . Pidd forms a complex with Raidd and procaspase-2 that is known as the 'Piddosome'. The Piddosome forms when DNA damage occurs and either activates NF-kappaB, leading to cell survival, or caspase-2, which leads to apoptosis .
Peptidase M66 domain (Peptidase_M66_dom)
Type: Domain

The peptidase family M66 domain is a zinc metalloprotease found in:

Enterohemorrhagic Escherichia coli (EHEC) neutral zinc metalloprotease StcE.

Aeromonas hydrophila ToxR-regulated lipoprotein TagA.

Vibrio cholerae ToxR-activated gene A lipoprotein TagA.

The peptidase family M66 domain adopts a characteristic mixed α+β and a conserved Met-turn, features that place it within the metzincin superfamily of metalloproteases including astacins, ADAMs (a disintegrin and metalloprotease) and matrixins. Notably, a central substrate-binding cleft containing the active site separates the peptidase family M66 domain into two subdomains SD1 and SD2. SD1 consists of a twisted β sheet packed on both sides by three helices. A sharp turn introduced by a conserved Gly in the zinc-binding motif along the active site helix then leads to SD2, which, after a series of convoluted loops, terminates in an helix. The peptidase family M66 coordinates an essential zinc ion in the characteristic tetrahedral fashion and possesses the extended zinc-binding motif HExxHxxGxxH .
Peptidase U49, Lit peptidase (Peptidase_U49_Lit_pept)
Type: Family

This entry consists of peptidases belonging to MEROPS peptidase family U49 (Lit peptidase, clan U-). The peptidase families associated with clan U- have an unknown catalytic mechanism as the protein fold of the active site domain and the active site residues have not been reported. The Lit peptidase from Escherichia coli functions in bacterial cell death in response to infection by Enterobacteria phage T4. Following binding of Gol peptide to domains II and III of elongation factor Tu, the Lit peptidase cleaves domain I of the elongation factor. This prevents binding of guanine nucleotides, shuts down translation and leads to cell death .
Peptidase U40 (Peptidase_U40)
Type: Family

Proteins in this entry include P5 murein endopeptidase from Pseudomonas phage phi6. P5 murein endopeptidase has lytic activity against several Gram-negative bacteria . It is thought that the enzyme cleaves the cell wall peptide bridge formed by meso-2,6-diaminopimelic acid and D-Alanine.
Peptidase inhibitor, PinA (Pept-inhibitor_PinA)
Type: Family

PinA inhibits the endopeptidase La. It binds to the La homotetramer but does not interfere with the ATP binding site or the active site of La.
Protease A inhibitor IA3 (Pai3)
Type: Family

The IA3 polypeptide of Saccharomyces cerevisiae (also known as Pai3) is an 8kDa inhibitor of the vacuolar aspartic proteinase (proteinase A or saccharopepsin, MEROPS peptidase family A1). It belongs to MEROPS inhibitor family I34, clan JA. No other aspartic proteinase has been found to be inhibited by IA3, and at least 15 aspartic proteinases related to YprA cleave IA3 as a substrate. Ligand- free IA3 has little intrinsic secondary structure, however, upon contact with proteinase A, residues 2-32 of the inhibitor become ordered and adopt a near perfect α-helical conformation occupying the active site cleft of the enzyme. This potent, specific interaction is directed primarily by hydrophobic interactions made by three key features in the inhibitory sequence .
Proteinase inhibitor I48, clitocypin (Prot_inh_I48_clitocypin)
Type: Family

Clitocypin binds and inhibits cysteine proteinases. It has no similarity to any other known cysteine proteinase inhibitors but bears some similarity to a lectin-like family of proteins from mushrooms . Insecticidal potential of clytocypins has been studied on colorado potato beetle, and thus, these are promising candidates for biopesticides .
Carboxypeptidase inhibitor I68 (Carboxypeptidase_inhibitor_I68)
Type: Family

This entry represents a family of tick carboxypetidase inhibitors . They accelerates fibrinolysis and may contribute to the maintenance of host blood liquidity during feeding.
A-kinase anchor protein 7-like, phosphoesterase domain (AKAP7-like_phosphoesterase)
Type: Domain

This entry represents the phosphoesterase domain found in the cyclic AMP-dependent protein kinase A (PKA) anchor protein, AKAP7 (also known as AKAP18). This domain belongs to the 2H RNA-phosphoesterase family and contains two conserved His-x-Thr motifs which, from structural studies, it has been suggested to bind AMP and CMP. It may act as a phosphoesterase, although its substrate has not been yet identified, or as an AMP sensor with the potential to couple intracellular AMP levels to PKA signalling events . This protein anchors PKA for its role in regulating PKA-mediated gene transcription in both somatic cells and oocytes, through its C-terminal RI-RII subunit-binding domain . AKAP7 also carries a nuclear localisation signal (NLS) KKRKK, that indicates the cellular destiny of this anchor protein .

The domain is also found in ASCC1 (activating signal cointegrator 1 complex subunit 1) , referred to as the C-terminal RNA ligase-like domain closely related to that in AKAP7, and in leukocyte receptor cluster member 9 whose function is unclear. This domain lacks residues critical for ligase activity, and in ASCC1 plays an important role in the regulation of the ASCC complex localization upon alkylation damage .