SII-SWORD/CoKE huggingface dataset:
RPB5-like RNA polymerase subunit superfamily (RPB5-like_sf)
Type: Homologous_superfamily

This entry represents a two-layer α/β fold, with a core structure of β/α/β/α/β(2) found in prokaryotic subunit H and the C terminus of eukaryotic RPB5.

Prokaryotes contain a single DNA-dependent RNA polymerase (RNAP;

) that is responsible for the transcription of all genes, while eukaryotes have three classes of RNAPs (I-III) that transcribe different sets of genes. Each class of RNA polymerase is an assemblage of ten to twelve different polypeptides. Certain subunits of RNAPs, including RPB5 (POLR2E in mammals), are common to all three eukaryotic polymerases. RPB5 plays a role in the transcription activation process. Eukaryotic RPB5 has a bipartite structure consisting of a unique N-terminal region (

), plus a C-terminal region that is structurally homologous to the prokaryotic RPB5 homologue, subunit H (gene rpoH) .
Spermadhesin, CUB domain superfamily (Sperma_CUB_dom_sf)
Type: Homologous_superfamily

The CUB domain (for complement C1r/C1s, Uegf, Bmp1) is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated . These proteins are involved in a diverse range of functions, including complement activation, developmental patterning, tissue repair, axon guidance and angiogenesis, cell signalling, fertilisation, haemostasis, inflammation, neurotransmission, receptor-mediated endocytosis, and tumour suppression . Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin). Proteins containing a CUB domain include:

Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.

Cricetidae sp. (Hamster) serine protease Casp, which degrades type I and IV collagen and fibronectin in the presence of calcium.

Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.

Vertebrate enteropeptidase (

), a type II membrane protein of the intestinal brush border, which activates trypsinogen.

Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.

Sea urchin blastula proteins BP10 and SpAN.

Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5.

Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.

Fibropellins I and III from Strongylocentrotus purpuratus (Purple sea urchin).

Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.

Mammalian spermadhesins.

Xenopus laevis embryonic protein UVS.2, which is expressed during dorsoanterior development.

Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains. Some CUB domains appear to be involved in oligomerisation and/or recognition of substrates and binding partners. For example, in the complement proteases, the CUB domains mediate dimerisation and binding to collagen-like regions of target proteins (e.g. C1q for C1r/C1s). The structure of CUB domains consists of a β-sandwich with a jelly-roll fold. Almost all CUB domains contain four conserved cysteines that probably form two disulphide bridges (C1-C2, C3-C4). The CUB1 domains of C1s and Map19 have calcium-binding sites .

Structurally, the spermadhesins consist of a CUB domain .
Plakin repeat superfamily (Plakin_repeat_sf)
Type: Homologous_superfamily

Plectin may have a role in cross-linking intermediate filaments, in inter-linking intermediate filaments with microtubules and microfilaments and in anchoring intermediate filaments to the plasma and nuclear membranes. Plectin is recruited into hemidesmosomes, multiprotein complexes that facilitate adhesion of epithelia to the basement membrane, thereby providing linkage between the intracellular keratin filaments to the laminins of the extracellular matrix. Plectin binds to hemidesmosomes through association of its actin-binding domain with the first pair of fibronectin type III repeats and a small part of the connecting segment of the integrin-beta4 subunit, the latter (integrin-alpha6,beta4) acting as a receptor for the extracellular matrix component laminin-5.

The plectin repeat is also seen in the cell adhesion junction plaque proteins, desmoplakin, envoplakin, and bullous pemphigoid antigen. The domains in plakins show considerable sequence homology. The N terminus consists of a plakin domain containing a number of subdomains with high α-helical content, while the central coiled-coil domain is composed of heptad repeats involved in the dimerisation of plakin, and the C terminus contains one or more homologous repeat sequences referred to plectin repeats . This entry represents the plectin repeats found in the C terminus of plakin proteins.
Egg-lysin superfamily (Egg_lysin_sf)
Type: Homologous_superfamily

This entry represents Egg-lysin from Haliotis rufescens and similar proteins from molluscs. This protein, also known as Sperm-lysin, binds to the egg vitelline envelope (VE) via the VE receptor for lysin (VERL) following its release from sperm. It then dissolves the VE non-enzymatically to create a hole, thereby allowing the sperm to pass through the envelope and fuse with the egg . Structurally, this protein consists of a bundle of helices and show species-specific binding to their egg receptor, possibly through differences in charged surface residues .
YjbQ-like superfamily (YjbQ-like_sf)
Type: Homologous_superfamily

This family contains small uncharacterised proteins of 14 to 16kDa mainly from bacteria although the signatures also occur in a hypothetical protein from archaea and eukaryotes. Members of this protein family, designated YjbQ in E. coli, have been studied extensively by crystallography. Members from several different species have been shown to have sufficient thiamine phosphate synthase activity ([ec:2.5.1.3)) to complement thiE mutants. However, it is presumed that this is a secondary activity, and the primary function of the YjbQ family enzyme remains unknown .
Delta-endotoxin CytB-like superfamily (CytB_endotoxin-like_sf)
Type: Homologous_superfamily

Bacillus thuringiensis produces the delta-endotoxin CytB, a membrane pore-forming protein, which is active against insects . The toxin kills the larvae of dipteran insects by making pores in the epithelial cell membrane of the insect midgut. The crystal protein is produced during sporulation and is accumulated both as an inclusion and as part of the spore coat.
EAL domain superfamily (EAL_sf)
Type: Homologous_superfamily

This domain is found in diverse bacterial signalling proteins. It is called EAL after its conserved residues. The EAL domain has been shown to stimulate degradation of a second messenger, cyclic di-GMP , and is a good candidate for a diguanylate phosphodiesterase function. Together with the GGDEF domain, EAL might be involved in regulating cell surface adhesiveness in bacteria . The domain contains many conserved acidic residues that could participate in metal binding and might form the phosphodiesterase active site. It often but not always occurs along with

and

domains that are also found in many signalling proteins
.
YhbY-like superfamily (YhbY-like_sf)
Type: Homologous_superfamily

Escherichia coli YhbY is associated with pre-50S ribosomal subunits, which implies a function in ribosome assembly. GFP fused to a single-domain CRM protein from maize localises to the nucleolus, suggesting that an analogous activity may have been retained in plants . A CRM domain containing protein in plant chloroplasts has been shown to function in group I and II intron splicing . In vitro experiments with an isolated maize CRM domain have shown it to have RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes . YhbY has a fold similar to that of the C-terminal domain of translation initiation factor 3 (IF3C), which binds to 16S rRNA in the 30S ribosome .
F/V-ATP synthase subunit C superfamily (F/V-ATP_Csub_sf)
Type: Homologous_superfamily

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

The F-ATPases (or F1F0-ATPases) and V-ATPases (or V1V0-ATPases) are each composed of two linked complexes: the F1 or V1 complex contains the catalytic core that synthesizes/hydrolyses ATP, and the F0 or V0 complex that forms the membrane-spanning pore. The F- and V-ATPases all contain rotary motors, one that drives proton translocation across the membrane and one that drives ATP synthesis/hydrolysis .

In V-ATPases, there are three proteolipid subunits (c, c' and c'') that form part of the proton-conducting pore, each containing a buried glutamic acid residue that is essential for proton transport, and together they form a hexameric ring spanning the membrane .
3H domain superfamily (3H_dom_sf)
Type: Homologous_superfamily

The transcription regulator TM1602 from Thermotoga maritima is a DNA-binding protein thought to belong to a family of de novo NAD synthesis pathway regulators. TM1602 has an N-terminal DNA-binding domain and a C-terminal 3H regulatory domain. The N-terminal domain appears to bind to the NAD promoter region and repress the de novo NAD biosynthesis operon, while the C-terminal 3H domain may bind to nicotinamide, nicotinic acid, or other substrate/products . The 3H domain has a 2-layer α/β sandwich fold.
TT1751-like domain superfamily (TT1751-like_sf)
Type: Homologous_superfamily

This domain superfamily is found in an undescribed set of proteins. It normally occurs uniquely within a sequence, but is found as a tandem repeat (

). It has an interesting phylogenetic distribution with the majority of examples in bacteria and archaea, but it is also found in Drosophila melanogaster (e.g.

). The hypothetical protein TT1751 from Thermus thermophilus has a β-α-β(4)-α structural fold .
FlaG-like superfamily (FlaG-like_sf)
Type: Homologous_superfamily

This entry includes protein FlaG (encoded from the flagellin locus) and an uncharacterised protein, YvyC, whose structure has been solved . In Aeromonas caviae, mutation of FlaG does not affect motility but does significantly reduce the level of its adherence to HEp-2 cells .
BSD domain superfamily (BSD_dom_sf)
Type: Homologous_superfamily

The BSD domain is an about 60-residue long domain named after the BTF2-like transcription factors, Synapse-associated proteins and DOS2-like proteins in which it is found. Additionally, it is also found in several hypothetical proteins. The BSD domain occurs in one or two copies in a variety of species ranging from primal protozoan to human. It can be found associated with other domains such as the BTB domain (see

) or the U-box in multidomain proteins. The function of the BSD domain is unknown .

Secondary structure prediction indicates the presence of three predicted α helices, which probably form a three-helical bundle in small domains. The third predicted helix contains neighbouring phenylalanine and tryptophan residues - less common amino acids that are invariant in all the BSD domains identified and that are the most striking sequence features of the domain .

Some proteins known to contain one or two BSD domains are listed below:

Mammalian TFIIH basal transcription factor complex p62 subunit (GTF2H1).

Yeast RNA polymerase II transcription factor B 73kDa subunit (TFB1), the homologue of BTF2.

Yeast DOS2 protein. It is involved in single-copy DNA replication and ubiquitination.

Drosophila synapse-associated protein SAP47.

Mammalian SYAP1.

Arabidopsis thaliana (Mouse-ear cress) TFB1-1 (TFB1A) and TFB1-3 (TFB1C).
NusB-like superfamily (NusB-like_sf)
Type: Homologous_superfamily

NusB is a prokaryotic transcription factor involved in antitermination processes, during which it interacts with the boxA portion of the mRNA nut site. Previous studies have shown that NusB exhibits an all-helical fold, and that the protein from Escherichia coli forms monomers, while Mycobacterium tuberculosis NusB is a dimer. The functional significance of NusB dimerization is unknown.

An N-terminal arginine-rich sequence is the probable RNA binding site, exhibiting aromatic residues as potential stacking partners for the RNA bases. The RNA binding region is hidden in the subunit interface of dimeric NusB proteins, such as NusB from M. tuberculosis, suggesting that such dimers have to undergo a considerable conformational change or dissociate for engagement with RNA. In certain organisms, dimerization may be employed to package NusB in an inactive form until recruitment into antitermination complexes .
DUSP-like superfamily (DUSP-like_sf)
Type: Homologous_superfamily

Deubiquitinating enzymes (DUB) form a large family of cysteine protease that can deconjugate ubiquitin or ubiquitin-like proteins (see

) from ubiquitin-conjugated proteins. All DUBs contain a catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain (see

) .
CoaB-like superfamily (CoaB-like_sf)
Type: Homologous_superfamily

CoaB adopts a 3-layer α/β/α fold with mixed β-sheets, which topologically resembles a combination of Rossmann-like and ribokinase-like folds. This structural domain can be found in human phosphopantothenoylcysteine (PPC) synthetase and CoaB from the Escherichia coli coenzyme A bifunctional protein CoaBC . The structure of these proteins predicts a ping pong mechanism with initial formation of an acyladenylate intermediate, followed by release of pyrophosphate and attack by cysteine to form the final products PPC and AMP.
FomD-like superfamily (FomD-like_sf)
Type: Homologous_superfamily

This group of prokaryotic proteins includes Nucleoside triphosphate/diphosphate phosphatase from Staphylococcus aureus (SA1684 or Ntdp), Cytidylyl-2-hydroxypropylphosphonate hydrolase from Streptomyces wedmorensis (FomD), and Probable ribonuclease FAU-1 from Pyrococcus abyssi.

SA1684 (

) shows nucleoside phosphatase activity towards nucleoside triphosphates and nucleoside diphosphates. It a significant effect on the proliferation of S. aureus colonies and the killing ability of the host .

FomD is a protein encoded in the fosfomycin biosynthesis gene cluster , which hydrolyses (S)-HPP-CMP to give (S)-HPP and CMP in the presence of Mn2 or Co2 . It also hydrolyses cytidylyl 2-hydroxyethylphosphonate (HEP-CMP), which is a biosynthetic intermediate before C-methylation. FomD structure revealed that it has a β-barrel fold consisting of a large twisted antiparallel β-sheet. It has a conserved Tyr residue which activates a water molecule to promote nucleophilic attack on the phosphorus atom of the phosphonate moiety .
YlxR-like superfamily (YlxR-like_sf)
Type: Homologous_superfamily

This entry represents the YlxR protein of unknown function from Streptococcus pneumonia. YlxR is expressed from the nusA/infB operon in bacteria and belongs to a small protein family (COG2740) that shares a conserved sequence motif GRGA(Y/W). The YlxR structure resembles a two-layer α/β sandwich with the overall shape of a cylinder. Structural analysis revealed that the YlxR structure represents a new protein fold that belongs to the α-β plait superfamily. YlxR is supposed to be an RNA-binding protein .
HflD-like superfamily (HflD-like_sf)
Type: Homologous_superfamily

When bacteriophage lambda infects to the Escherichia coli cell, it undergoes either lytic growth or lysogenization. The lambda CII protein is a key determinant in the lysis-lysogeny decision. Escherichia coli HflD is a factor that may sequesters CII from the target promoters and recruits it to the membrane where the FtsH protease is localized .
Hypothetical protein MTH1880 (MTH1880)
Type: Homologous_superfamily

MTH1880 is a hypothetical protein from Methanobacterium thermoautotrophicum. The structure has an α/β fold. The molecular surface of the protein reveals a small, highly acidic pocket comprising loop B, the end of beta2, and loop D, indicating that the protein would have a possible cation binding site. It is proposed that the MTH1880 protein may function as a calcium buffering protein .
Phage tail protein-like superfamily (Phage_tail_protein-like_sf)
Type: Homologous_superfamily

This entry represents bacteriophage lambda, GpU, a minor tail protein. GpU plays an essential role in tail assembly by capping the rapidly polymerizing tail once it has reached its requisite length and serving as the interaction surface for the completion protein . The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.

This entry also includes some uncharacterised proteins from bacteria, such as Gp37 and putative cytoplasmic protein STM4215.
TFB5-like superfamily (TFB5-like_sf)
Type: Homologous_superfamily

This entry represents TTDA/Tfb5 subunit of TFIIH basal transcription factor complex. These proteins have a structural motif consisting of a 2-layer sandwich structure with an α/β plait topology. Nucleotide excision repair is a major pathway for repairing UV light-induced DNA damage in most organisms.

Transcription/repair factor IIH (TFIIH) is essential for RNA polymerase II transcription and nucleotide excision repair. The TFIIH multiprotein complex consists of a 7-subunit core (XPB, p62, p52, p44, p34, and TTDA) that is associated with a 3-subunit CDK-activating kinase module (MAT1, cyclin H and Cdk7) .

In humans, defects in TTDA cause the trichothiodystrophy photosensitive (TTDP), an autosomal recessive disease characterised by sulfur-deficient brittle hair and nails, ichthyosis, mental retardation, impaired sexual development, abnormal facies and cutaneous photosensitivity correlated with a nucleotide excision repair (NER) defect .
BB2672 superfamily (BB2672)
Type: Homologous_superfamily

BB2672 are structurally similar to proteins with the Bacillus chorismate mutase-like (BCM-like) fold. Their structure, combined with its genomic context, suggest that they have a role in amino acid synthesis .
Formamidopyrimidine-DNA glycosylase, N-terminal (FPG_N)
Type: Homologous_superfamily

This entry represents the catalytic domain of DNA glycosylase/AP lyase enzymes including formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei).

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) are trifunctional DNA base excision repair enzymes that remove a wide range of oxidation-damaged bases (N-glycosylase activity;

) and cleave both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity;

). Fpg has a preference for oxidised purines, excising oxidised purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). Its AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge . The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidised base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes . Fpg binds one ion of zinc at the C-terminal, which contains four conserved and essential cysteines .

Endonuclease VIII (Nei) has the same enzyme activities as Fpg (

,

), but with a preference for oxidised pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine . These proteins contain three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger . The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a β-hairpin loop formed by the zinc finger .
Hemerythrin-like superfamily (Hemerythrin-like_sf)
Type: Homologous_superfamily

The hemerythrin family is composed of hemerythrin proteins found in invertebrates, and a broader collection of bacterial and archaeal homologues. Hemerythrin is an oxygen-binding protein found in the vascular system and coelomic fluid, or in muscles (myohemerythrin) in invertebrates . Many of the homologous proteins found in prokaryotes are multi-domain proteins with signal-transducing domains such as the GGDEF diguanylate cyclase domain (

) and methyl-accepting chemotaxis protein (MCP) signalling domain (

). Most hemerythrins are oxygen-carriers with a bound non-haem iron, but at least one example is a cadmium-binding protein, apparently with a role in sequestering toxic metals rather than in binding oxygen. The prokaryote with the most instances of this domain is Magnetococcus sp. MC-1, a magnetotactic bacterium.

Hemerythrins and myohemerythrins are small proteins of about 110 to 129 amino acid residues that bind two iron atoms. They are left-twisted 4-α-helical bundles, which provide a hydrophobic pocket where dioxygen binds as a peroxo species, interacting with adjacent aliphatic side chains via van der Waals forces . In both hemerythrins and myohemerythrins, the active centre is a binuclear iron complex, bound directly to the protein via 7 amino acid side chains , 5 His, 1 Glu and 1 Asp . Ovohemerythrin , a yolk protein from the leech Theromyzon tessulatum seems to belong to this family of proteins, it may play a role in the detoxification of free iron after a blood meal .