SII-SWORD/CoKE huggingface dataset:
Haemophore, haem-binding domain superfamily (MHB_sf)
Type: Homologous_superfamily

This entry represents a coiled-coil domain that binds free haem in mycobacterial cytoplasm to deliver it to membrane proteins for shuttling through the membrane .
SecE superfamily (SecE_sf)
Type: Homologous_superfamily

Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component . From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.

The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecCY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) . The chaperone protein SecB is a highly acidic homotetrameric protein that exists as a "dimer of dimers" in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion . SecE, part of the main SecYEG translocase complex, is ~106 residues in length, and spans the inner membrane of the Gram-negative bacterial envelope. Together with SecY and SecG, SecE forms a multimeric channel through which preproteins are translocated, using both proton motive forces and ATP-driven secretion. The latter is mediated by SecA. The structure of the Escherichia coli SecYEG assembly revealed a sandwich of two membranes interacting through the extensive cytoplasmic domains . Each membrane is composed of dimers of SecYEG. The monomeric complex contains 15 transmembrane helices.
Small ribosomal subunit protein bS21 superfamily (Ribosomal_bS21_sf)
Type: Homologous_superfamily

The small ribosomal subunit protein bS21 contains 55-70 amino acid residues, and it was thought to be present only in eubacteria, however, plant chloroplasts and mammalian mitochondria contain a ribosomal subunit protein bS21 (referred to as bS21c and bS21m, respectively). Experimental evidence has revealed that S21 is well exposed on the surface of the Escherichia coli ribosome , and is one of the 'split proteins': these are a discrete group that are selectively removed from 30S subunits under low salt conditions and are required for the formation of activated 30S reconstitution intermediate (RI*) particles.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
DNA replication regulator HobA superfamily (HobA_sf)
Type: Homologous_superfamily

Proteins in this superfamily are approximately 180 amino acids in length found exclusively in epsilon-proteobacteria. The crystal structure of HobA from Helicobacter pylori has been reported at 1.7A resolution; HobA represents a modified Rossmann fold consisting of a five-stranded parallel β-sheet (β1-5) flanked on one side by α2, α3 and α6 helices and α4 and α5 on the other. The α1 helix is extended away from and has minimal interaction with the globular part of the protein. Four monomers interact to form a tetrameric molecule. Four calcium atoms bind to the tetramer and these binding sites may have functional relevance. The closest structural homologue of HobA is a sugar isomerase (SIS) domain containing protein, the phosphoheptose isomerase from Pseudomonas aeruginosa. The SIS proteins share strong sequence homology with DiaA from Escherichia coli; yet, HobA and DiaA share no sequence homology .
Ste5, Fus3-binding domain superfamily (Ste5_C_sf)
Type: Homologous_superfamily

The Saccharomyces cerevisiae pheromone response pathway involves a cascade of 3 MAP kinases Ste11, Ste7, and Fus3. Ste5 is the prototypical scaffold protein involved in the coordination of the yeast mating mitogen-activated protein kinase (MAPK) response by binding to all three components of the MAPK cascade (Ste11, Ste7 and Fus3) and serving as a required co-activator of the mating-specific MAPK, Fus3 . This entry represents the C-terminal Fus3-binding domain of Ste5, also known as the minimal scaffold domain. It acts as a co-catalyst, binding Fus3 and promoting its phosphorylation by Ste7. In the absence of this domain, Fus3 is an extremely poor substrate for Ste7. The requirement for both Ste7 and this domain in Fus3 activation ensures that Fus3 is selectively activated by the mating pathway and not by other pathways that also utilise Ste7 .
CGT/MARTX, cysteine protease (CPD) domain superfamily (CPD_dom_sf)
Type: Homologous_superfamily

Large bacterial protein toxins autotranslocate functional effector domains to the eukaryotic cell cytosol, resulting in alterations to cellular functions that ultimately benefit the infecting pathogen. Among these toxins, the clostridial glucosylating toxins (CGTs) produced by Gram-positive bacteria and the multifunctional-autoprocessing RTX (MARTX) toxins of Gram-negative bacteria have distinct mechanisms of post-translocation, but a shared mechanism of post-translocation autoprocessing that releases these functional domains from the large holotoxins. These toxins carry an embedded cysteine protease domain (CPD) that is regulated by a unique allosteric activation mechanism. Binding of the eukaryotic-specific small molecule inositol hexakisphosphate (InsP(6)) to a basic cleft within the CPD induces a structural rearrangement that exposes the protease active site to its substrates. Proteins containing this domain belong to the peptidase family C80 of clan CD .

The CGT/MARTX CPD domain consists of a central β-sheet that is surrounded by α-helices. Additional β-strands at the C terminus form a subdomain known as the β-flap, that is loosely attached to the core protease. The CGT/MARTX CPD catalytic dyad is composed of one His and one Cys residue. The distance between the catalytic residues indicates that the Cys is not activated by protonation from His, but rather suggests that the Cys is substrate-activated by close alignment of the scissile bond, while the His functions solely to protonate the leaving group .
Formate dehydrogenase, C-terminal domain superfamily (Formate_DH_C_sf)
Type: Homologous_superfamily

This superfamily represents the C-terminal transmembrane domain of formate dehydrogenase.

The transmembrane domain of the beta subunit of formate dehydrogenase consists of a single transmembrane helix. This domain acts as a transmembrane anchor, allowing the conduction of electrons within the protein .
Threonylcarbamoyl-AMP synthase, C-terminal domain superfamily (Sua5/YwlC_C)
Type: Homologous_superfamily

This domain can be found in the C terminus of threonylcarbamoyl-AMP synthases, including Sua5 from Saccharomyces cerevisiae and YwlC from Bacillus subtilis.
Threonylcarbamoyl-AMP synthase is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t6A37) in tRNAs that read codons beginning with adenine .

This domain adopts the Rossmann fold and may be involved in GTP and/or tRNA binding based on structural similarity with both GTP and tRNA binding proteins .
Beta-thymosin superfamily (Beta-thymosin_sf)
Type: Homologous_superfamily

This entry represents beta-thymosin superfamily. Its members include thymosin beta-4, -10, -15 from humans and their homologues (such as thymosin beta 11/12) from fish.

Thymosin beta-4 (Tbeta) is a small protein that sequesters actin monomers to help maintain the high concentrations of unpolymerised actin in higher eukaryotic cells. Its structure has been resolved . It is a multiple function protein that plays important roles in cellular processes such as wound healing, embryonic organ development and the pathogeneses of disease . It plays a role in anti-apoptotic response to an external stress , paclitaxel-resistance via ROS production and HIF-1alpha stabilisation via Erk activation . It also regulates cancer cell migration through various signalling pathways, and hence plays a role in malignant progression and invasion in colon adenocarcinoma .
Bacteriochlorophyll c-binding superfamily (Bchl_C-bd_sf)
Type: Homologous_superfamily

Chlorosomes, which are attached to the inner surface of the cytoplasmic membrane, consist of four polypeptides and associated pigments and lipids. The principal light-harvesting pigment of the green filamentous bacterium Chloroflexus aurantiacus is bacteriochlorophyll (Bchl) c. This pigment is either bound to, or constrained by, a small approximately 80-residue polypeptide designated Bchlc-binding protein. In C. aurantiacus, a C-terminal extension is believed to play a role in proper incorporation of the protein during chlorosome assembly . The protein has a high degree of similarity to Bchlc-binding proteins of other photosynthetic bacteria.
RcsC, C-terminal domain superfamily (RcsC_C_sf)
Type: Homologous_superfamily

This domain is found in the C terminus of the signal transduction response regulator (phospho-relay) kinase RcsC, between the ATP-binding region (

) and the receiver region. This domain forms a discrete α/β/loop structure . The Rcs signalling pathway controls a variety of physiological functions like capsule synthesis, cell division or motility in prokaryotes. The Rcs regulation cascade, involving a multi-step phosphorelay between the two membrane-bound hybrid sensor kinases RcsC and RcsD and the global regulator RcsB, is, up to now, one of the most complicated regulatory systems in bacteria .
Proteasome assembly chaperone 2 superfamily (PSMG2_sf)
Type: Homologous_superfamily

This superfamily represents PAC2 (Proteasome assembly chaperone) proteins found in bacteria, archaea and eukaryotes. Its C-terminal segment containing the potential proteasome-activating HbYX motif. These proteins function as a chaperone for the 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass and contains one 20S core particle structure and two 19S regulatory caps. The 26S proteasome mediates ubiquitin-dependent proteolysis in eukaryotic cells. A number of studies including very recent ones have revealed that assembly of its 20S catalytic core particle is an ordered process that involves several conserved proteasome assembly chaperones (PACs). Two heterodimeric chaperones, PAC1-PAC2 and PAC3-PAC4, promote the assembly of rings composed of seven alpha subunits .
Metal-sensitive repressor, helix protomer superfamily (Metal_Tscrpt_repr_sf)
Type: Homologous_superfamily

The overall protomer fold consists of three α-helices of varying lengths, organised in a closed tetrameric assembly . This superfamily includes metal-sensitive repressors involved in resistance to metal ions. Members of this superfamily bind copper, nickel or cobalt ions via conserved cysteine and histidine residues. In the absence of metal ions, these proteins bind to promoter regions and repress transcription. When bound to metal ions they are unable to bind DNA, leading to transcriptional derepression .
L-fucose isomerase, domain 1 superfamily (Fucose_iso_dom1_sf)
Type: Homologous_superfamily

Proteins containing this domain are similar to L-fucose isomerase expressed by Escherichia coli (

,

). This enzyme corresponds to glucose-6-phosphate isomerase in glycolysis, and converts an aldo-hexose to a ketose to prepare it for aldol cleavage. The enzyme is a hexamer, with each subunit being wedge-shaped and composed of three domains. Both domains 1 and 2 contain central parallel β-sheets with surrounding α helices. Domain 1 demonstrates the β-α-β-α-β Rossman fold. The active centre is shared between pairs of subunits related along the molecular three-fold axis, with domains 2 and 3 from one subunit providing most of the substrate-contacting residues, and domain 1 from the adjacent subunit contributing some other residues .

This entry represents the domain 1 of L-fucose isomerase.
L-fucose isomerase, domain 2 superfamily (Fucose_isomerase_dom2_sf)
Type: Homologous_superfamily

Proteins containing this domain are similar to L-fucose isomerase expressed by Escherichia coli (

,

). This enzyme corresponds to glucose-6-phosphate isomerase in glycolysis, and converts an aldo-hexose to a ketose to prepare it for aldol cleavage. The enzyme is a hexamer, with each subunit being wedge-shaped and composed of three domains. Both domains 1 and 2 contain central parallel β-sheets with surrounding α-helices. The active centre is shared between pairs of subunits related along the molecular three-fold axis, with domains 2 and 3 from one subunit providing most of the substrate-contacting residues .

This entry represents the domain 2 of L-fucose isomerase.
L-fucose isomerase, domain 3 superfamily (Fuc_iso_dom3_sf)
Type: Homologous_superfamily

Proteins containing this domain are similar to L-fucose isomerase expressed by Escherichia coli (

,

). This enzyme corresponds to glucose-6-phosphate isomerase in glycolysis, and converts an aldo-hexose to a ketose to prepare it for aldol cleavage. The enzyme is a hexamer, with each subunit being wedge-shaped and composed of three domains. Both domains 1 and 2 contain central parallel β-sheets with surrounding α-helices. The active centre is shared between pairs of subunits related along the molecular three-fold axis, with domains 2 and 3 from one subunit providing most of the substrate-contacting residues .

This entry represents the domain 3 of L-fucose isomerase.
TA0956 superfamily (TA0956_sf)
Type: Homologous_superfamily

TA0956 is a protein from Thermoplasma acidophilum which currently has no known function however the structure has been determined. The protein has a two-layered α/β-sandwich topology and is a putative Elongation factor 1-alpha binding motif .
SpoIIAA-like superfamily (SpoIIAA-like_sf)
Type: Homologous_superfamily

These proteins adopt an α/β SpoIIAA-like fold, similar to the one found in STAT

. They adopt opened and closed conformations arising from different arrangements of their α2 and α3 helices. They may be membrane associated and may function as carriers of non-polar compounds .
TBCC, N-terminal domain superfamily (TBCC_N_sf)
Type: Homologous_superfamily

Tubulin binding cofactor C (TBCC) is a post-chaperonin involved in folding pathways that lead to the final release of alpha beta native heterodimers incorporated in microtubules. TBCC is organised into three different domains: N-terminal, CARP and C-terminal .

This entry represents the N-terminal domain of TBCC. The N-terminal comprises a structured coiled coil and a highly dynamic N-terminal region which concentrates 80% of charged and polar residues and is believed to be important in interaction with tubulin . Overall, the N-terminal domain of TBCC is responsible for its interaction with components of the centrosome by its N-terminal domain.
NAB co-repressor domain 2 superfamily (NCD2_sf)
Type: Homologous_superfamily

Nab1 and Nab2 are co-repressors that specifically interact with and repress transcription mediated by the three members of the NGFI-A (Egr-1, Krox24, zif/268) family of eukaryotic (metazoa) transcription factors . This entry represents a NAB domain 2 of the protein. It is necessary for transcriptional repression by the Nab proteins . It is also required for transcription activation by Nab proteins at Nab-activated promoters .
Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus (NSP3_SUD-M_sf_bCoV)
Type: Homologous_superfamily

The multi-domain non-structural protein NSP3 is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. While some of the domains differ between CoV genera, eight domains of NSP3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. There are also two transmembrane regions, TM1 and TM2, which exist in all CoVs .

SUD consists of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C . Among these, SUD-N and SUD-M are macrodomains. The SUD-N domain is a related macrodomain which also binds G-quadruplexes . While SUD-N is specific to the NSP3 of SARS and betacoronaviruses of the sarbecovirus subgenera (B lineage), SUD-M is present in most NSP3 proteins except the NSP3 from betacoronaviruses of the embecovirus subgenera (A lineage). SUD-M, despite its name, is not specific to SARS. SUD-C adopts a frataxin-like fold, has structural similarity to DNA-binding domains of DNA-modifying enzymes, binds single-stranded RNA, and regulates the RNA binding behavior of the SUD-M macrodomain. SARS-CoV Nsp3 contains a third macrodomain (the X-domain). The X-domain may function as a module binding poly(ADP-ribose); however, SUD-N and SUD-M do not bind ADP-ribose, as the triple glycine sequence involved in its binding is not conserved in these .
Rev1, C-terminal domain superfamily (Rev1_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain of DNA repair protein Rev1, an enzyme which allows DNA synthesis to proceed even in the presence of DNA damage. Rev1 belongs to the Y-family of TLS polymerases. Rev1 possess a limited catalytic activity but it has a second and more important function which involved the recruitment and coordination of other Y-family TLS polymerases and the regulatory subunit Rev7 of the B-family polymerase pol. This interaction is mediated by its C-terminal domain which therefore serves as a scaffold that allows access of the Y-family polymerases to their cognate DNA lesions and the subsequent exchange to pol, which then extends the distorted DNA primer terminus opposite the lesion . This domain adopts a four-helix bundle that interacts with Rev7, Polkappa and Poleta. However, the Rev7-binding interface is distinct from the binding site of DNA polymerase eta or kappa .
Restriction endonuclease, type II, PvuII superfamily (PvuII_sf)
Type: Homologous_superfamily

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 .

This entry represents the type II restriction endonuclease PvuII, which recognise the double-stranded DNA sequence 5'-CAGCTG-3' and cleave after G-3 .
Plasmodium falciparum UIS3, C-terminal domain superfamily (PfUIS3_sf)
Type: Homologous_superfamily

UIS3 is a membrane protein essential for sporozoite development in infected hepatocytes. This superfamily corresponds to the 130-229 region of the Plasmodium falciparum UIS3 protein which is compact and has an all α-helical structure. PfUIS3(130-229) interacts with lipids, phospholipid lysosomes, the human liver fatty acid-binding protein and with the lipid phosphatidylethanolamine. The interaction with liver fatty acid-binding protein provides the parasite with a method to import essential fatty acids/lipids during rapid growth phases of sporozoites .
TRAP transporter solute receptor DctP superfamily (TRAP_DctP_sf)
Type: Homologous_superfamily

The tripartite ATP-independent periplasmic (TRAP) transporters are substrate-binding protein (SBP)-dependent secondary transporters found in prokaryotes. They consist of a substrate-binding protein (SBP) of the DctP or TAXI families and two integral membrane proteins that form the DctQ and DctM protein families .

DctP is part of the DctP-TRAP (tripartite ATP-independent periplasmic) transporter involved in binding extracellular solutes for transport across the bacterial cytoplasmic membrane. Proteins in this family include DctP from R. capsulatus, SiaP from Haemophilus influenzae , DctB from Bacillus subtilis , and TeaA from Halomonas elongata . The structure of the SiaP receptor has revealed an overall topology similar to ATP binding cassette ESR (extracytoplasmic solute receptors) proteins . Upon binding of sialic acid, SiaP undergoes domain closure about a hinge region and kinking of an α-helix hinge component .
Cytochrome oxidase Caa3-type, subunit IV superfamily (Caa3-IV_sf)
Type: Homologous_superfamily

Cytochrome c oxidase, a haem copper oxidase superfamily member, is the final step in the electron-transport chain, linking O
2
reduction to transmembrane pumping in mitochondria and aerobic prokaryotes. Cytochrome c oxidase (aka Complex IV) catalyzes the reduction of O
2
to 2H
2
O, and acts downstream of Complexes I-III: NADH-Q oxidoreductase, succinate-Q reductase, and Q-cytochrome c oxidoreductase. In Thermus thermophilus caa3-oxidase is comprised of subunit (SU) I/III, a fusion of classical SU I and SU III, and IIc as well SU IV, which is composed of two connected transmembrane helices that interface with SU I/III .
DUF3837 superfamily (DUF3837_sf)
Type: Homologous_superfamily

This entry represents a small, compact all-α helical domain of unknown function. This domain is currently only found in Clostridiales species.