SII-SWORD/CoKE huggingface dataset:
Multiheme cytochrome superfamily (Multihaem_cyt_sf)
Type: Homologous_superfamily

In proteins belonging to the c-type cytochrome family , the haem group is covalently attached by thioether bonds to two conserved cysteine residues located in the cytochrome c centre. Cytochromes c typically function in electron transfer, but c-type cytochrome centres are also found in the active sites of many enzymes.

This domain contains multiple CxxCH motifs. There are a variable number of helices, as well as a little β structure present in multihaem cytochromes, but they do not form a true structural fold. Cytochrome (cyt) c3-like proteins are multihaem cytochromes, including cyt c3 with four haem groups , cyt c7 (cyt c551.5) with three haem groups (deletion of one cyt c3 haem-binding site), nine-haem cyt c (tandem repeat of two cyt c3-like domains with an additional haem-binding site), and 16-haem cyt c HmcA (tandem repeat of four cyt c3-like domains). The photosynthetic reaction centre composed of a cytochrome subunit is also a multihaem cytochrome . In addition, the di-haem elbow motif shows a similar structure, the main characteristic feature of this motif being the packing of its two haems; many members of this group of proteins contain one or more complete motifs flanked by incomplete motifs and/or other domains. For example, the di-haem elbow motif is present in the multihaem cytochrome domain found in the periplasmic nitrate reductase subunit NapB , in hydroxylamine oxioreductase HAO (contains 3 complete motifs), in cyt c554 (contains one complete motif), in cyt c nitrite reductase, and in the N-terminal domain of flavocytochrome c3 (respiratory fumarate reductase).
SinR repressor/SinI anti-repressor, dimerisation domain superfamily (SinR/SinI_dimer_dom_sf)
Type: Homologous_superfamily

The SinR repressor is part of a group of Sin (sporulation inhibition) proteins in Bacillus subtilis that regulate the commitment to sporulation in response to extreme adversity . SinR is a tetrameric repressor protein that binds to the promoters of genes essential for entry into sporulation and prevents their transcription. This repression is overcome through the activity of SinI, which disrupts the SinR tetramer through the formation of a SinI-SinR heterodimer, thereby allowing sporulation to proceed. The SinR structure consists of two domains: a dimerisation domain stabilised by a hydrophobic core, and a DNA-binding domain that is identical to domains of the bacteriophage 434 CI and Cro proteins that regulate prophage induction. The dimerisation domain is a four-helical bundle formed from two helices from the C-terminal residues of SinR and two helices from the central residues of SinI. These regions in SinR and SinI are similar in both structure and sequence. The interaction of SinR monomers to form tetramers is weaker than between SinR and SinI, since SinI can effectively disrupt SinR tetramers.

This entry represents the dimerisation domain in both SinI and SinR proteins.

The structure of the SinR dimerisation domain consists of an intertwined heterodimer of two homologous chains.
Glutathione S-transferase, C-terminal domain superfamily (Glutathione-S-Trfase_C_sf)
Type: Homologous_superfamily

In eukaryotes, glutathione S-transferases (GSTs) participate in the detoxification of reactive electrophillic compounds by catalysing their conjugation to glutathione. GST is found as a domain in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli. The major lens polypeptide of cephalopods is also a GST . Bacterial GSTs of known function often have a specific, growth-supporting role in biodegradative metabolism: epoxide ring opening and tetrachlorohydroquinone reductive dehalogenation are two examples of the reactions catalysed by these bacterial GSTs. Some regulatory proteins, like the stringent starvation proteins, also belong to the GST family . GST seems to be absent from Archaea in which gamma-glutamylcysteine substitute to glutathione as major thiol.

Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The homodimeric enzymes display a conserved structural fold. Each monomer is composed of a distinct N-terminal sub-domain, which adopts the thioredoxin fold, and a C-terminal all-helical sub-domain, which adopts a 4-helical bundle fold. This entry is the C-terminal domain.

Glutaredoxin 2 (Grx2), glutathione-dependent disulphide oxidoreductases, is structurally similar to GSTs, even though they lack any sequence similarity. Grx2 is also composed of N and C-terminal subdomains. It is thought that the primary function of Grx2 is to catalyse reversible glutathionylation of proteins with glutathione in cellular redox regulation including the response to oxidative stress. Grx2 is dissimilar to other glutaredoxins apart from containing the conserved active site residues .
NOB1 zinc finger-like superfamily (NOB1_Zf-like_sf)
Type: Homologous_superfamily

This entry corresponds to a zinc ribbon and is found on the RNA binding protein NOB1.
G-protein gamma-like domain superfamily (GGL_sf)
Type: Homologous_superfamily

This entry represents the G protein gamma subunit and the GGL (G protein gamma-like) domain superfamily, which are related in sequence and are comprised of an extended α-helical polypeptide. The G protein gamma subunit forms a stable dimer with the beta subunit, but it does not make any contact with the alpha subunit, which contacts the opposite face of the beta subunit. The GGL domain is found in several RGS (regulators of G protein signaling) proteins. GGL domains can interact with beta subunits to form novel dimers that prevent gamma subunit binding, and may prevent heterotrimer formation by inhibiting alpha subunit binding. The interaction between G protein beta-5 neuro-specific isoforms and RGS GGL domains may represent a general mode of binding between β-propeller proteins and their partners .

The G protein structure consists of a long α-helix interrupted in the middle.
PRP4-like superfamily (PRP4-like_sf)
Type: Homologous_superfamily

This small domain is found on PRP4 ribonuleoproteins. PRP4 is a U4/U6 small nuclear ribonucleoprotein that is involved in pre-mRNA processing . It is also found in pre-mRNA-splicing factor 18 .
LexA/Signal peptidase-like superfamily (LexA/Signal_pep-like_sf)
Type: Homologous_superfamily

This entry represents a structural domain superfamily found in serine peptidases belonging to MEROPS peptidase families: S24 (LexA family, clan SF); S26A (signal peptidase I), S26B (signalase) and S26C TraF peptidase. This domain has a complex fold made of several coiled β-sheets, which contains an SH3-like barrel structure.

The S26 family includes Escherichia coli signal peptidase, SPase, which is a membrane-bound endopeptidase with two N-terminal transmembrane segments and a C-terminal catalytic region . SPase functions to release proteins that have been translocated into the inner membrane from the cell interior, by cleaving off their signal peptides. In SPase proteins, this domain is disrupted by the insertion of an additional all-beta subdomain.

Note: This signature covers both the SH3-like barrel β-ribbon domain and the all-β subdomain inserted into it.

The S24 family includes:

the lambda repressor CI/C2 family and related bacterial prophage repressor proteins .

LexA, the diverse family of bacterial transcription factors that repress genes in the cellular SOS response to DNA damage .

MucA and the related UmuD proteins, which are lesion-bypass DNA polymerases, induced in response to mitogenic DNA damage . UmuD is self-processed by its own serine protease activity during the SOS response.

RulA, a component of the rulAB locus that confers resistance to UV.

All of these proteins, with the possible exception of RulA, interact with RecA, which activates self cleavage either derepressing transcription in the case of CI and LexA or activating the lesion-bypass polymerase in the case of UmuD and MucA. UmuD'2, is the homodimeric component of DNA pol V, which is produced from UmuD by RecA-facilitated self-cleavage. The first 24 N-terminal residues of UmuD are removed; UmuD'2 is a DNA lesion bypass polymerase . MucA , like UmuD, is a plasmid encoded a DNA polymerase (pol RI) which is converted into the active lesion-bypass polymerase by a self-cleavage reaction involving RecA .

This group of proteins also contains proteins not recognised as peptidases as well as those classified as non-peptidase homologues as they either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for catalytic activity.
Rv1873-like superfamily (Rv1873-like_sf)
Type: Homologous_superfamily

This is a superfamily of uncharacterised proteins. The structure of one of the members in this superfamily has been solved and it adopts a mainly α helical structure.
Aconitase B, HEAT-like domain superfamily (Aconitase_B_HEAT-like_dom_sf)
Type: Homologous_superfamily

Aconitase (aconitate hydratase;

) is an iron-sulphur protein that contains a [4Fe-4S]-cluster and catalyses the interconversion of isocitrate and citrate via a cis-aconitate intermediate. Aconitase functions in both the TCA and glyoxylate cycles, however unlike the majority of iron-sulphur proteins that function as electron carriers, the [4Fe-4S]-cluster of aconitase reacts directly with an enzyme substrate. In eukaryotes there is a cytosolic form (cAcn) and a mitochondrial form (mAcn) of the enzyme. In bacteria there are also 2 forms, aconitase A (AcnA) and B (AcnB). Several aconitases are known to be multi-functional enzymes with a second non-catalytic, but essential function that arises when the cellular environment changes, such as when iron levels drop . Eukaryotic cAcn and mAcn, and bacterial AcnA have the same domain organisation, consisting of three N-terminal α/β/α domains, a linker region, followed by a C-terminal 'swivel' domain with a β/β/α structure (1-2-3-linker-4), although mAcn is small than cAcn. However, bacterial AcnB has a different organisation: it contains an N-terminal HEAT-like domain, followed by the 'swivel' domain, then the three α/β/α domains (HEAT-4-1-2-3) .

This entry represents the N-terminal HEAT-like domain superfamily, which is present in bacterial aconitase (AcnB), but not in AcnA or eukaryotic cAcn/IRP2 or mAcn. This domain consists of 10 α helices, forming two curved layers in a right-handed α-α superhelix. The first and last α helix interact with another domain within aconitate B, while the middle 8 form a structure made up of four repeating units. This HEAT-like domain is also referred to as domain 5. The helices from domain 5 pack against domain 4 to form a funnel-like structure towards the active site, implicating domain 5 in protein-protein interactions. The HEAT-like domain and the 'swivel' domain that follows it were shown to be sufficient for dimerisation and for AcnB binding to mRNA. An iron-mediated dimerisation mechanism may be responsible for switching AcnB between its catalytic and regulatory roles, as dimerisation requires iron while mRNA binding is inhibited by iron.
Hypothetical protein YfhH (YfhH)
Type: Homologous_superfamily

This entry consists of a group of proteins predominantly found in Firmicutes, including Uncharacterized protein YfhH from Bacillus subtilis and protein GK0453 from Geobacillus kaustophilus. GK0453 shows two small domains: an helix-turn-helix like motif is found in its N-terminal domain while an SH3-like β-barrel like structure is observed its C-terminal region. Its specific function is unknown . Some of the members of this protein family are annotated as being transcriptional regulators (see

,

).
Phenylalanine zipper superfamily (Phe_ZIP_sf)
Type: Homologous_superfamily

The phenylalanine zipper consists of aromatic side chains from ten phenylalanine residues that are stacked within a hydrophobic core. This zipper mediates dimerisation of various proteins, such as APS, SH2-B and Lnk .
NAD(P)-binding domain superfamily (NAD(P)-bd_dom_sf)
Type: Homologous_superfamily

This entry represents NAD- and NADP-binding domains superfamily with a core Rossmann-type fold, which consists of three layers (α/β/α) with parallel β-sheet of 6 strands. Many different enzymes contain an NAD/NADP-binding domain, including:

C-terminal domain of alcohol dehydrogenases

Tyrosine-dependent oxidoreductases (also known as short-chain dehydrogenases)

N-terminal domain of glyceraldehyde-3-phosphate dehydrogenase

NAD-binding domain of formate/glycerate dehydrogenases

N-terminal domain of sirohaem synthase

N-terminal domain of lactate dehydrogenase

N-terminal domain of 6-phosphogluconate dehydrogenase (the β-sheet is extended to 8 strands)

C-terminal domain of amino acid dehydrogenases (an extra N-terminal helix displaces the C-terminal helix

NAD-binding domain of certain potassium channels

C-terminal domain of the transcriptional repressor Rex

Ornithine cyclodeaminase

CoA-binding N-terminal domain of the alpha chain of succinyl-CoA synthetase
Proline/betaine transporter ProP, C-terminal (ProP_C)
Type: Homologous_superfamily

The osmosensory transporter coiled coil is a C-terminal domain found in various bacterial osmoprotective transporters, such as ProP, Proline/betaine transporter, Proline permease 2 and the citrate proton symporters. It adopts an antiparallel coiled-coil structure, and is essential for osmosensory and osmoprotectant transporter function .
Rbstp2229-like superfamily (Rbstp2229-like_sf)
Type: Homologous_superfamily

This superfamily consists of hypothetical proteins produced by Bacilli.
GlgS superfamily (GlgS_sf)
Type: Homologous_superfamily

GlgS (surface composition regulator) is a major determinant of cell surface composition. It negatively regulates motility, adhesion and synthesis of biofilm exopolysaccharides in Escherichia coli . The structure of the polypeptide chain comprises a bundle of two parallel amphipathic helices, α1 and α3, and a short hydrophobic helix α2 sandwiched between them .
SKP1-like, dimerisation domain superfamily (SKP1-like_dim_sf)
Type: Homologous_superfamily

SKP1 (together with SKP2) was identified as an essential component of the cyclin A-CDK2 S phase kinase complex . It was found to bind several F-box containing proteins (e.g., Cdc4, Skp2, cyclin F) and to be involved in the ubiquitin protein degradation pathway. A yeast homologue of SKP1 (P52286) was identified in the centromere bound kinetochore complex and is also involved in the ubiquitin pathway . In Dictyostelium discoideum (Slime mold) FP21 was shown to be glycosylated in the cytosol and has homology to SKP1 .

This entry represents the superfamily of a dimerisation domain found at the C-terminal of SKP1 proteins , as well as in subunit D of the centromere DNA-binding protein complex Cbf3 . This domain is multi-helical in structure, and consists of an interlocked herterodimer in F-box proteins.
PG0816-like superfamily (PG0816-like_sf)
Type: Homologous_superfamily

This superfamily contains a set of hypothetical bacterial proteins.
Chalcone isomerase superfamily (Chalcone_isomerase_sf)
Type: Homologous_superfamily

Chalcone isomerase (CHI,

; also known as chalcone-flavanone isomerase) is a plant enzyme responsible for the isomerisation of chalcone to naringenin, a key step in the biosynthesis of flavonoids. The Petunia hybrida (Petunia) genome contains two genes coding for very similar enzymes, ChiA and ChiB, but only the first seems to encode a functional chalcone isomerase. Chalcone isomerase has a core 2-layer α/β structure consisting of β(3)-α(2)-β-α(2)-β(3) .

Altered inheritance of mitochondria protein 18/46, mitochondrial (AIM18/16) are CHI-like proteins from Saccharomyces cerevisiae, which lacks other enzymes of the flavonoid pathway. They show a similar fold to CHI with an extra fungal-specific loop. Instead of the chalcone isomerase activity these proteins bind heme, and structural prediction suggest this domain might be related to bacterial cytochrome P460 .

This entry represents the chalcone isomerases domain found in proteins from plants, fungi and bacteria.
Polyketide synthase, docking domain superfmaily (Polyketide_synth_docking_sf)
Type: Homologous_superfamily

The N-terminal docking domain found in modular polyketide synthase assumes an α-helical structure, wherein two α-helices are connected by a short loop. Two such N-terminal domains dimerise to form amphipathic parallel α-helical coiled coils: dimerisation is essential for protein function .
Mir domain superfamily (MIR_dom_sf)
Type: Homologous_superfamily

This entry represents the MIR domain superfamily.

The MIR domain is named after three of the proteins in which it occurs: protein Mannosyltransferase (

), Inositol 1,4,5-trisphosphate receptor (IP3R) and Ryanodine receptor (RyR). MIR domains have also been found in eukaryotic stromal cell-derived factor 2 (SDF-2) and in Chlamydia trachomatis protein CT153. The MIR domain may have a ligand transferase function. This domain has a closed β-barrel structure with a hairpin triplet, and has an internal pseudo-threefold symmetry. The MIR motifs that make up the MIR domain consist of ~50 residues and are often found in multiple copies.

Inositol 1,4,5-trisphosphate (InsP3) is an intracellular second messenger that transduces growth factor and neurotransmitter signals. InsP3 mediates the release of Ca
2+
from intracellular stores by binding to specific Ca
2+
channel-coupled receptors. Ryanodine receptors are involved in communication between transverse-tubules and the sarcoplamic reticulum of cardiac and skeletal muscle. The proteins function as a Ca
2+
-release channels following depolarisation of transverse-tubules . The function is modulated by Ca
2+
, Mg2+, ATP and calmodulin. Deficiency in the ryanodine receptor may be the cause of malignant hyperthermia (MH) and of central core disease of muscle (CCD) . protein O-mannosyltransferases transfer mannose from DOL-P-mannose to ser or thr residues on proteins.
Necrosis inducing protein-1 superfamily (NIP1_sf)
Type: Homologous_superfamily

Necrosis inducing protein-1 (NIP1) is a small phytotoxic protein secreted by the barley pathogen Rhynchosporium secalisconsists. It is a fungal avirulence protein on host plants of the Rrs1 resistance genotype . NIP1 consists of two parts containing β-sheets of two and three anti-parallel strands, respectively. Five intramolecular disulphide bonds stabilise these parts and their position with respect to each other, providing a high level of stability .
Pyosin/cloacin translocation domain superfamily (Pyosin/cloacin_T_dom_sf)
Type: Homologous_superfamily

This entry represents a structural domain superfamily with a complex fold made of several coiled β-sheets. This domain is found at the N-terminal of both colicin E3 and colicin B, and acts as a translocation domain. It also occurs in S-type pyocin. Both pyocin and cloacin are bacteriocins, protein antibiotics that kill bacteria closely related to the producing species. Colicins are a subgroup of bacteriocins that are produced by and target Escherichia coli. The lethal action of most colicins is exerted either by formation of a pore in the cytoplasmic membrane of the target cell, or by an enzymatic nuclease digestion mechanism .
Cag-Z superfamily (Cag-Z_sf)
Type: Homologous_superfamily

Helicobacter pylori (Campylobacter pylori) clinical isolates can be classified into two types according to their degree of pathogenicity. Type I strains are associated with a severe disease pathology, express functional VacA (vacuolating cytotoxin A) and contain an insertion of 40 kb of foreign DNA: the cag (cytotoxin-associated gene) pathogenicity island (cagPAI). Type II strains lack the 40 kb insert, cagPAI. The cagPAI may be divided into two regions, cag I and cag II and contain approximately 16 and 15 genes, respectively. The cagPAI encodes a type IV secretion system (T4SS), which delivers CagA into the cytosol of gastric epithelial cells through a rigid needle structure covered by Cag7 or CagY, a VirB10-homologous protein, and CagT, a VirB7-homologous protein, at the base . The CagA protein is the virulence factor that induces morphological changes in host cells, which may be associated with the development of peptic ulcer and gastric carcinoma .

CagZ is a 23kDa protein consisting of a single compact L-shaped domain, composed of seven α-helices that run antiparallel to each other and 70% of the residues are in α-helix conformation: no β-sheet is present. CagZ is essential for the translocation of the pathogenic protein CagA into host cells .
Hypothetical protein MTH1184 (MTH1184)
Type: Homologous_superfamily

Members of this superfamily consist of a β-sheet region followed by an α-helix and an unstructured C terminus. The β-sheet region contains a CXCX...XCXC sequence with Cys residues located in two proximal loops and pointing towards each other. This precise function of this set of archaeal proteins is, as yet, unknown .
RGS domain superfamily (RGS_sf)
Type: Homologous_superfamily

This entry represents a structural domain superfamily with a multi-helical fold consisting of a 4-helical bundle with a left-handed twist and an up-and-down topology. This domain can be divided into two all-alpha subdomains. This domain is found in regulation of G-protein signalling (RGS) proteins, as well as other related proteins, including:

RGS4 .

RGS9 .

G-alpha interacting protein GaIP .

Axin .

p115RhoGEF .

Pdz-RhoGEF .

G-protein coupled receptor kinase 2 N-terminal domain .

RGS (Regulator of G Protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit (

), which can then bind the beta-gamma dimer (

,

) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.

All RGS proteins contain an 'RGS-box' (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are comprised of little more than an RGS domain, while others also contain additional domains that confer further functionality. RGS domains can be found in conjunction with a variety of domains, including: DEP for membrane targeting (

), PDZ for binding to GPCRs (

), PTB for phosphotyrosine-binding (

), RBD for Ras-binding (

), GoLoco for guanine nucleotide inhibitor activity (

), PX for phosphatidylinositol-binding (

), PXA that is associated with PX (

), PH for stimulating guanine nucleotide exchange (

), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (

). Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.
ISWI, HAND domain superfamily (ISWI_HAND-dom_sf)
Type: Homologous_superfamily

Nucleosome remodelling is an energy-dependent process that alters histone-DNA interactions within nucleosomes, thereby rendering nucleosomal DNA accessible to regulatory factors. The ATPases involved belong to the SWI2/SNF2 subfamily of DEAD/H-helicases, which contain a conserved ATPase domain characterised by seven motifs. Proteins within this family differ with regard to domain organisation, their associated proteins and the remodelling complex in which they reside.