SII-SWORD/CoKE huggingface dataset:
Hemocyanin, C-terminal domain superfamily (Hemocyanin_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain superfamily of hemocyanin and hexamerin proteins.

Crustacean and cheliceratan hemocyanins (oxygen-transport proteins) and insect hexamerins (storage proteins) are homologous gene products, although the latter do not bind oxygen .

Haemocyanins are found in the haemolymph of many invertebrates. They are divided into 2 main groups, arthropodan and molluscan. These have structurally similar oxygen-binding centres, which are similar to the oxygen-binding centre of tyrosinases, but their quaternary structures are arranged differently. The arthropodan proteins exist as hexamers comprising 3 heterogeneous subunits (a, b and c) and possess 1 oxygen-binding centre per subunit; and the molluscan proteins exist as cylindrical oligomers of 10 to 20 subunits and possess 7 or 8 oxygen-binding centres per subunit . Although the proteins have similar amino acid compositions, the only real similarity in their primary sequences is in the region corresponding to the second copper-binding domain, which also shows similarity to the copper-binding domain of tyrosinases.
RnfH superfamily (RnfH_sf)
Type: Homologous_superfamily

RnfH is a member of the ubiquitin superfamily. Members of the RnfH family strongly co-occur in two distinct gene neighbourhood contexts. In one it is associated with a START domain protein, a membrane protein SmpA and the transfer mRNA binding protein SmpB. This association suggests a possible role in the SmpB-tmRNA-based tagging and degradation system of bacteria, which is interesting given that other members of the ubiquitin system are analogously involved in protein-tagging and degradation across eukaryotes and various prokaryotes. The second context in which the RnfH genes are present is in a membrane associated complex involved in transporting electrons for various reductive reactions such as nitrogen fixation .
Formyl transferase, C-terminal domain superfamily (Formyl_trans_C_sf)
Type: Homologous_superfamily

Methionyl-tRNA formyltransferase (

) transfers a formyl group onto the amino terminus of the acyl moiety of the methionyl aminoacyl-tRNA. The formyl group appears to play a dual role in the initiator identity of N-formylmethionyl-tRNA by promoting its recognition by IF2 and by impairing its binding to EFTU-GTP. This family also includes formyltetrahydrofolate dehydrogenases, which produce formate from formyl-tetrahydrofolate. These enzymes contain an N-terminal domain in common with other formyl transferase enzymes (

). The C-terminal domain has an open β-barrel fold .
[NiFe]-hydrogenase, small subunit, N-terminal domain superfamily (NiFe_Hase_small_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain superfamily of periplasmic [NiFe] hydrogenase small subunit, hydrogenase-1 small chain and uptake hydrogenase small subunit.

Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases . Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.

The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.

The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion . Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms.
Photosystem II cytochrome b559, alpha subunit superfamily (PSII_cyt_b559_asu_sf)
Type: Homologous_superfamily

Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product .

PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane . Within the core of the complex, the chlorophyll and β-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection .

This entry represents the alpha subunit (PsbE) superfamily of cytochrome b559, which forms a haem-binding heterodimer with the beta subunit (PsbF) (

) within the reaction centre core of PSII. Both PsbE and PsbF are essential components for PSII assembly, and are probably involved in secondary electron transport mechanisms that help to protect PSII from photo-damage .
Vgr protein, OB-fold domain superfamily (Vgr_OB-fold_dom_sf)
Type: Homologous_superfamily

This domain occurs in a family of phage (and bacteriocin) proteins related to the phage P2 V gene product, which forms the small spike at the tip of the tail . Homologs in general are annotated as baseplate assembly protein V. At least one member is encoded within a region of Pectobacterium carotovorum (Erwinia carotovora) described as a bacteriocin, a phage tail-derived module able to kill bacteria closely related to the host strain.

It is also found in Vgr-related proteins. Genes encoding type VI secretion systems (T6SS) are widely distributed in pathogenic Gram-negative bacterial species. In Vibrio cholerae, T6SS have been found to secrete three related proteins extracellularly, VgrG-1, VgrG-2, and VgrG-3. VgrG-1 can covalently cross-link actin in vitro, and this activity was used to demonstrate that V. cholerae can translocate VgrG-1 into macrophages by a T6SS-dependent mechanism. VgrG-related proteins likely assemble into a trimeric complex that is analogous to that formed by the two trimeric proteins gp27 and gp5 that make up the baseplate "tail spike" of Escherichia coli bacteriophage T4. The VgrG components of the T6SS apparatus might assemble a "cell-puncturing device" analogous to phage tail spikes to deliver effector protein domains through membranes of target host cells .

Gp5 is an integral component of the virion baseplate of bacteriophage T4. T4 Gp5 consists of 3 domains connected via long linkers: the N-terminal oligosaccharide/oligonucleotide-binding (OB)-fold domain, the middle lysozyme domain, and the C-terminal triplestranded-helix. The equivalent of the Gp5 OB-fold domain in the structure of VgrG is the domain of unknown function comprising residues 380-470 and conserved in all known VgrGs. This entry represents the OB-fold domain which consists of a 5-stranded antiparallel-barrel with a Greek-key topology .
YqgF/RNase H-like domain superfamily (YqgF/RNaseH-like_dom_sf)
Type: Homologous_superfamily

The YqgF domain superfamily is described as RNase H-like and typified by the Escherichia coli protein YqgF .YqgF domain-containing proteins are predicted to be ribonucleases or resolvases based on homology to RuvC Holliday junction resolvases.

The group of proteins containing this domain are found primarily in the low-GC Gram-positive bacteria Holliday junction resolvases (HJRs) and in eukaryote orthologs. The RuvC HJRs are conspicuously absent in the low-GC Gram-positive bacterial lineage, with the exception of Ureaplasma urealyticum(

, ). Furthermore, loss of function ruvC mutants of Escherichia coli show a residual HJR activity that cannot be ascribed to the prophage-encoded RusA resolvase . This suggests that the YqgF family proteins could be alternative HJRs whose function partially overlaps with that of RuvC .

The functions of eukaryotic proteins having this domain are less well described. In Saccharomyces cerevisiae (Baker's yeast) Spt6p and its orthologues, the catalytic residues are substituted indicating that they lack the enzymatic function of resolvases . Spt6p has been implicated in transcription initiation and in maintaining normal chromatin structure during transcription elongation .

Horizontal gene transfer, lineage-specific gene loss and gene family expansion, and non-orthologous gene displacement seem to have been major forces in the evolution of HJRs and related nucleases. The diversity of HJRs and related nucleases in bacteria and archaea contrasts with their near absence in eukaryotes. The few detected eukaryotic representatives of the endonuclease fold and the RNase H fold have probably been acquired from bacteria via horizontal gene transfer. The identity of the principal HJR(s) involved in recombination in eukaryotes remains uncertain; this function could be performed by topoisomerase IB or by a novel, so far undetected, class of enzymes. Likely HJRs and related nucleases were identified in the genomes of numerous bacterial and eukaryotic DNA viruses. Gene flow between viral and cellular genomes has probably played a major role in the evolution of this class of enzymes.

The YqgF domain is also found in Tex proteins, where maintains the core structural elements and aligns especially well with RuvC nucleases, although Tex does not appear to possess nuclease activity . Tex (toxin expression) is a highly conserved bacterial protein involved in expression of critical toxin genes .
Dr-adhesin superfamily (Dr_adhesin_sf)
Type: Homologous_superfamily

Dr-adhesin bind the Dr blood group antigen component of decay-accelerating factor. These proteins contain both fimbriated and afimbriated adherence structures and mediate adherence of uropathogenic Escherichia coli to the urinary tract . They also confer the mannose-resistant hemagglutination phenotype, which can be inhibited by chloramphenicol. The N-terminal portion of the mature protein is thought to be responsible for chloramphenicol sensitivity .

Afa/Dr adhesins display an afimbrial/fimbrial morphology and are exported to the bacterial surface by the chaperone-usher pathway, a widespread system among gram-negative pathogens for the secretion of fimbrial proteins . AfaD protein caps the AfaE fibrils, where it can efficiently perform its role as an invasin .

The structure of the AfaD domain exhibits an Immunoglobulin-like topology where the two β-sheets pack against each other in an analogous fashion to AfaE and archetypal pilin domains. The AfaD role as an initiator of the fimbrial assembly and the cap of the fibrillar structure is defined by the absence of a free N-terminal extension .
Alliinase, N-terminal domain superfamily (Alliinase_N_sf)
Type: Homologous_superfamily

Allicin is a thiosulphinate that gives rise to dithiines, allyl sulphides and ajoenes, the three groups of active compounds in Allium species. Allicin is synthesised from sulphoxide cysteine derivatives by alliinase, whose C-S lyase activity cleaves C(beta)-S(gamma) bonds. It is thought that this enzyme forms part of a primitive plant defence system .

This entry represents the N-terminal domain, which is involved in substrate binding .

The N-terminal domain of tryptophan aminotransferase-related proteins from plants is also found in this entry. This tryptophan aminotransferase is thought to be involved in auxin (IAA) biosynthesis, where it is required for auxin production to initiate multiple change in growth in response to environmental and developmental cues .
Retinal cGMP phosphodiesterase, gamma subunit superfamily (PDE6_gamma_sf)
Type: Homologous_superfamily

Retinal rod and cone cGMP phosphodiesterases function as the effector enzymes in the vertebrate visual transduction cascade. This entry represents the inhibitory gamma subunit , which is also expressed outside retinal tissues and has been shown to interact with the G-protein-coupled receptor kinase 2 signalling system to regulate the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney 293 cells .

The gamma subunit is intrinsically disordered and its interaction with the alpha subunit involves the selection of preconfigured transient conformations .
Succinylarginine dihydrolase superfamily (AstB_sf)
Type: Homologous_superfamily

Succinylarginine dihydrolase (AstB) transforms N(2)-succinylglutamate into succinate and glutamate. This enzyme is the second in the five-step ammonia-producing arginine succinyltransferase pathway, the major pathway in Escherichia coli and in other related bacteria for arginine catabolism as a sole nitrogen source. AstB assumes a five-stranded α/β propeller structure, placing it in the amidinotransferase (AT) superfamily of proteins, which are characterised by their Cys-His-Glu active site triad .
DNA-directed RNA polymerase, subunit 2, hybrid-binding domain superfamily (DNA-dir_RNAP_su2_hyb_sf)
Type: Homologous_superfamily

RNA polymerases (

) catalyse the DNA dependent polymerisation of RNA. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). This entry represents the hybrid-binding and the wall domain superfamily . The hybrid-binding domain binds the nascent RNA strand/template DNA strand in the Pol II transcription elongation complex. This domain contains the important structural motifs, switch 3 and the flap loop and binds an active site metal ion . It is also involved in binding to Rpb1 and Rpb3 . Many of the bacterial members contain large insertions within this domain, which are known as dispensable region 2 (DRII).
RNA polymerase Rpb2, domain 2 superfamily (RNA_pol_Rpb2_2_sf)
Type: Homologous_superfamily

RNA polymerases catalyse the DNA-dependent polymerisation of RNA. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). Rpb2 is the second largest subunit of the RNA polymerase. This domain forms one of the two distinctive lobes of the Rpb2 structure. It is also known as the lobe domain . DNA has been demonstrated to bind to the concave surface of the lobe domain, and plays a role in maintaining the transcription bubble. Many of the bacterial members contain large insertions within this domain, a region known as dispensable region 1 (DRI).
Glycerate kinase-like, C-terminal domain superfamily (GK-like_C_sf)
Type: Homologous_superfamily

Two groups of glycerate kinases are known. The first group consists of glycerate kinases from bacterial species, primarily of the Firmicutes group and the gamma subdivision of Proteobacteria. The second group includes TM1585 and glycerate kinases from eukaryotes and archaea in addition to several bacterial species. This entry represents the C-terminal domain of TM1585 and related glycerate kinases .
GMP phosphodiesterase, delta subunit superfamily (PDED_dom_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily found in GMP-PDE delta subunit and related proteins.
L-proline 3-hydroxylase, C-terminal domain superfamily (Pro_3_hydrox_C_sf)
Type: Homologous_superfamily

Iron (II)/2-oxoglutarate (2-OG)-dependent oxygenases catalyse oxidative reactions in a range of metabolic processes. Proline 3-hydroxylase hydroxylates proline at position 3, the first of a 2-OG oxygenase catalysing oxidation of a free alpha-amino acid. The structure contains conserved motifs present in other 2-OG oxygenases including a jelly roll strand core and residues binding iron and 2-oxoglutarate, consistent with divergent evolution within the extended family. The structure differs significantly from many other 2-OG oxygenases in possessing a discrete C-terminal helical domain .
tRNA nuclease HepT-like superfamily (HepT-like_sf)
Type: Homologous_superfamily

This entry describes prokaryotic proteins including tRNA nuclease HepT from Aphanizomenon flos-aquae, the toxic component of a type II toxin-antitoxin (TA) system comprising a minimal nucleotidyltransferase (MNT) and the accompanying HEPN (higher eukaryotes and prokaryotes nucleotide-binding) protein . HepT dimerises and enables the formation of a deep cleft at the HEPN-domain interface, containing the RX4-6H motif (where X is any amino acid and the residue immediately after the conserved R is typically a polar amino acid), the active site that functions as an RNA-cleaving RNase . HepT from Aphanizomenon flos-aquae targets a subset of tRNAs and cuts off 4 nt from the 3' end of tRNA acceptor stem, but its toxicity is neutralized by covalent di-AMPylation performed by the MNT antitoxin .
Chorismate mutase, AroQ class superfamily, eukaryotic (CM_AroQ_sf_eucaryotic)
Type: Homologous_superfamily

Chorismate mutase (CM) is a regulatory enzyme (

) required for biosynthesis of the aromatic amino acids phenylalanine and tyrosine. CM catalyzes the Claisen rearrangement of chorismate to prephenate, which can subsequently be converted to precursors of either L-Phe or L-Tyr. In bifunctional enzymes the CM domain can be fused to a prephenate dehydratase (P-protein for Phe biosynthesis), to a prephenate dehydrogenase (T-protein, for Tyr biosynthesis), or to 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase (

). Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur in prokaryotes as well as in fungi, plants and nematode worms .

The type I or AroH class of CM is represented by Bacillus subtilis aroH, a monofunctional, nonallosteric, homotrimeric enzyme characterised by its pseudo-α/β-barrel 3D structure. Each monomer folds into a 5-stranded mixed β-sheet packed against an α-helix and a 3-10 helix. The core is formed by a closed barrel of mixed β-sheets surrounded by helices. The interfaces between adjacent subunits form three equivalent clefts that harbor the active sites .

The type II or AroQ class of CM has a completely different all-helical 3D structure, represented by the CM domain of the bifunctional Escherichia coli P-protein. This type is named after the Enterobacter agglomerans monofunctional CM encoded by the aroQ gene . All CM domains from bifunctional enzymes as well as most monofunctional CMs belong to this class, including archaeal CM.

Eukaryotic CM from plants and fungi form a separate subclass of AroQ, represented by the Baker's yeast allosteric CM . These enzymes show only partial sequence similarity to the prokaryotic CMs due to insertions of regulatory domains, but the helix-bundle topology and catalytic residues are conserved and the 3D structure of the E. coli CM dimer resembles a yeast CM monomer . The E. coli P-protein CM domain consists of 3 helices and lacks allosteric regulation. The yeast CM has evolved by gene duplication and dimerisation, and each monomer has 12 helices. Yeast CM is allosterically activated by Trp and inhibited by Tyr .
Cytotoxic necrotizing factor, Rho-activating domain superfamily (CNF_Rho-act_sf)
Type: Homologous_superfamily

This domain superfamily is found in several bacterial cytotoxic necrotizing factor proteins as well as related dermonecrotic toxin (DNT) from Bordetella species .

Cytotoxic necrotizing factor 1 (CNF1) is a toxin whose structure from Escherichia coli revealed a 4-layer α/β/β/α structure containing mixed β-sheets . CNF1 is expressed in strains of E. coli causing uropathogenic and neonatal meningitis. CNF1 alters host cell actin cytoskeleton and promotes bacterial invasion of the blood-brain barrier endothelial cells . CNF1 belongs to a unique group of large cytotoxins that cause constitutive activation of Rho guanosine triphosphatases (GTPases), which are key regulators of the actin cytoskeleton .

Bordetella dermonecrotic toxin (DNT) stimulates the assembly of actin stress fibres and focal adhesions by deamidating or polyaminating Gln63 of the small GTPase Rho. DNT is an A-B toxin composed of an N-terminal receptor-binding (B) domain and a C-terminal enzymatically active (A) domain .
Trigger factor, C-terminal domain superfamily (Trigger_fac_C_sf)
Type: Homologous_superfamily

In the Escherichia coli cytosol, a fraction of the newly synthesised proteins requires the activity of molecular chaperones for folding to the native state. The major chaperones implicated in this folding process are the ribosome-associated Trigger Factor (TF), and the DnaK and GroEL chaperones with their respective co-chaperones. Trigger Factor is an ATP-independent chaperone and displays chaperone and peptidyl-prolyl-cis-trans-isomerase (PPIase) activities
in vitro
. It is composed of at least three domains, an N-terminal domain which mediates association with the large ribosomal subunit, a central substrate binding and PPIase domain with homology to FKBP proteins, and a C-terminal domain of unknown function. The positioning of TF at the peptide exit channel, together with its ability to interact with nascent chains as short as 57 residues renders TF a prime candidate for being the first chaperone that binds to the nascent polypeptide chains .

This entry represents the C-terminal domain superfamily of bacterial trigger factor proteins, which has a multi-helical structure consisting of an irregular array of long and short helices. This domain is structurally similar to the peptide-binding domain of the bacterial porin chaperone SurA.

This entry also matches foldase protein PrsA N-terminal region. PrsA plays an important role in protein secretion by helping the post-translocational extracellular folding of several secreted proteins .
Transcriptional regulator YdaT-like superfamily (YdaT-like_sf)
Type: Homologous_superfamily

YdaT is a transcriptional regulator whose expression significantly impairs bacterial growth and cell viability. It disrupts the expression of multiple regulons normally governed by RcsA, leading to defects in lipopolysaccharide biosynthesis and cell division. While YdaT has no impact on Rac prophage excision, its overexpression, particularly as part of the ydaST operon, has been linked to increased toxicity, morphological abnormalities, and further reductions in cell viability . YdaT toxin was first thought to be neutralised by the putative antitoxin YdaS (

) but recent studies showed that both YdaS and YdaT can act independently as toxins and are regulated by RacR .
Moricin domain superfamily (Moricin_sf)
Type: Homologous_superfamily

Moricin is a antibacterial peptide that is highly basic. The structure of moricin reveals that it is comprised of a long α-helix. The N terminus of the helix is amphipathic, and the C terminus of the helix is predominately hydrophobic. The amphipathic N-terminal segment of the α-helix is mainly responsible for the increase in permeability of the bacterial membrane which kills the bacteria .