SII-SWORD/CoKE huggingface dataset:
Arterivirus papain-like cysteine protease alpha (PCPalpha) domain superfamily (AV_PCPalpha_sf)
Type: Homologous_superfamily

Arteriviruses are enveloped, positive-stranded RNA viruses and include pathogens of major economic concern to the swine- and horse-breeding industries:

Equine arteritis virus (EAV).

Porcine reproductive and respiratory syndrome virus (PRRSV).

Mice actate dehydrogenase-elevating virus.

Simian hemorrhagic fever virus.

The arterivirus replicase gene is composed of two open reading frames (ORFs). ORF1a is translated directly from the genomic RNA, whereas ORF1b can be expressed only by ribosomal frameshifting, yielding a 1ab fusion protein. Both replicase gene products are multidomain precursor proteins which are proteolytically processed into functional nonstructural proteins (nsps) by a complex proteolytic cascade that is directed by four (PRRSV/LDV) or three (EAV) proteinase domains encoded in ORF1a. The arterivirus replicase processing scheme involves the rapid autoproteolytic release of two or three N-terminal nsps (nsp1 (or nsp1alpha/1beta) and nsp2) and the subsequent processing of the remaining polyproteins by the "main protease" residing in nsp4, together resulting in a set of 13 or 14 individual nsps.

The arterivirus nsp1 region contains a tandem of papain-like cysteine autoprotease domains (PCPalpha and PCPbeta), but in EAV PCPalpha has lost its enzymatic activity, resulting in the 'merge' of nsp1alpha and nsp1beta into a single nsp1 subunit. Thus, instead of three self-cleaving N-terminal subunits, EAV has two: nsp1 and nsp2. The PCPalpha and PCPbeta domains mediate the nsp1alpha|1beta and nsp1beta|2 cleavages, respectively. The catalytic dyad of PCPalpha and PCPbeta domains is composed of Cys and His residues. In EAV, a Lys residue is found in place of the catalytic Cys residue, which explains the proteolytic deficiency of the EAV PCPalpha domain . The PCPalpha and PCPbeta domains form respectively MEROPS peptidase families C31 and C32.

The PCPalpha and PCPbeta domains have a typical papain fold, which consists of a compact global region containing sequentially connected left (L) and right (R) parts in a so-called standard orientation. The L subdomain of PCPalpha consists of four α-helices, while the R subdomain is formed by three antiparallel β strands . The L subdomain of the PCBbeta consists of three α-helices, while the R subdomain is formed by four antiparallel β-strands . The Cys and His residues face each other at the L-R interface and form the catalytic centre of the PCPalpha and PCPbeta domains .

This entry represents the PCPalpha domain (peptidase C31) superfamily.
Phytochelatin synthase, N-terminal domain superfamily (PCS_N_sf)
Type: Homologous_superfamily

Phytochelatins are well known as the heavy metal-detoxifying peptides in higher plants, eukaryotic algae, fungi, nematode and cyanobacteria. Phytochelatin synthase (PCS, also known as glutathione gamma-glutamylcysteinyltransferase;

) is involved in the synthesis of phytochelatins (PC) and homophytochelatins (hPC). This enzyme is required for detoxification of heavy metals such as cadmium and arsenate. The N-terminal region of phytochelatin synthase contains the active site, as well as four highly conserved cysteine residues that appear to play an important role in heavy-metal-induced phytochelatin catalysis. The C-terminal region is rich in cysteines, and may act as a metal sensor, whereby the Cys residues bind cadmium ions to bring them into closer proximity and transferring them to the activation site in the N-terminal catalytic domain . The C-terminal region displays homology to the functional domains of metallothionein and metallochaperone.

This entry represents the N-terminal catalytic PCS domain superfamily. Proteins in this entry belong to the peptidase family C83 of the papain superfamily of cysteine proteases, with a structurally conserved "catalytic triad" and oxyanion hole in the active site. It has an overall "crescent" shape with α/β fold containing eight α-helices and six β-strands .
Ferrous iron transporter, core domain (FeoA_core_dom)
Type: Homologous_superfamily

This entry represents the core domain of the ferrous iron (Fe2+) transport protein FeoA found in bacteria. This domain also occurs at the C terminus in the diphtheria toxin repressor (DtxR). DtxR is a iron-binding repressor that contains two domains separated by a short linker. The C-terminal domain adopts a fold similar to eukaryotic Src homology 3 domains, but its functional role is unknown .

The transporter Feo is composed of three proteins: FeoA a small, soluble SH3-domain protein probably located in the cytosol; FeoB, a large protein with a cytosolic N-terminal G-protein domain and a C-terminal integral inner-membrane domain containing two 'Gate' motifs which likely functions as the Fe2+ permease; and FeoC, a small protein apparently functioning as an [Fe-S]-dependent transcriptional repressor . Feo allows the bacterial cell to acquire iron from its environment.
H-NOX domain superfamily (H-NOX_domain_sf)
Type: Homologous_superfamily

Heme-nitric oxide/oxygen binding (H-NOX) domains function as sensors for the gaseous signaling agent nitric oxide (NO) in eukaryotes and bacteria . They can also function as oxigen sensors, as is the case for soluble guanylate cyclases from Caenorhabditis elegans . The H-NOX fold consists of seven α-helices and one four-stranded antiparallel β sheet .
6-Cysteine (6-Cys) domain superfamily (6_CYS_dom_sf)
Type: Homologous_superfamily

The 6-Cysteine (6-Cys) domain is found in Plasmodium proteins that are expressed in all stages of the parasite life cycle in both the vertebrate and mosquito hosts. The domain is of roughly 120 amino acids and contains six positionally conserved cysteines. It might occur in 1-14 copies per protein, either as the sole globular domain or in combination wih β-helix-forming hexapeptide repeats as is the case of sequestrin. It is generally found in tandem pairs of A-type and B-type domains. Previously believed to be exclusive to Plasmodium, the 6-Cys domain also exists in proteins found in all members of the aconoidasidan (hematozoan) clade of Apicomplexa, which unites the haemosporidians (Plasmodium) and piroplasms) .

The 6-cys domain is a β-sandwich formed by two sheets with a mixture of parallel and antiparallel strands. Three disulfide bonds are present in the 6_Cys domain with C1-C2, C3-C6, and C4-C5 connectivity. C1-C2 and C3-C6 pin together the two sheets of the β-sandwich, whereas C4-C5 links an ancyllary loop to the core domain .
VirB9/CagX/TrbG, C-terminal domain superfamily (VirB9/CagX/TrbG_C_sf)
Type: Homologous_superfamily

VirB9 is a component of the type IV secretion system, which is employed by pathogenic bacteria to export virulence proteins directly from the bacterial cytoplasm into the host cell. Unlike the more common type III secretion system, type IV systems evolved from the conjugative apparatus, which is used to transfer DNA between cells. VirB9 was initially identified as an essential virulence gene on the Agrobacterium tumefaciens Ti plasmid. In the pilin-like conjugative structure, VirB9 appears to form a stabilizing complex in the outer membrane, by interacting with the lipoprotein VirB7. The heterodimer has been shown to stabilize other components of the type IV system .

This entry represents the C-terminal domain of VirB9. It is also found in TrbG, a probable conjugal transfer protein from Rhizobium and CagX, a component of the Helicobacter pylori cag PAI-encoded type IV secretion system .
Ig-like SoxY domain superfamily (SoxY_sf)
Type: Homologous_superfamily

This domain is found in the sulfur oxidation protein SoxY. Dissimilatory oxidation of thiosulfate is carried out by the ubiquitous sulfur-oxidizing (Sox) multi-enzyme system. In this system, SoxY plays a key role, functioning as the sulfur substrate-binding protein that offers its sulfur substrate, which is covalently bound to a conserved C-terminal cysteine, to another oxidizing Sox enzyme . The structure of this domain shows an Ig-like fold .

Many times it has been reported that SoxY strictly interacts with SoxZ to form a SoxYZ heterodimer. However, recent studies have shown this stable complex is not an obligate, and that the individual proteins may exist on their own. SoxY exhibits a dimer/tetramer equilibrium that is dependent on the redox state of the cysteines and on the type of sulfur substrate component bound to them. The SoxY tetramer consists of two dimeric β-sandwiches that interact with each other via two small interface patches at the tips of the dimers .
Drosophila transcription factor p53, C-terminal domain superfamily (Dro_p53_C_sf)
Type: Homologous_superfamily

The p53 tumour suppressor is a protein found in increased amounts in a wide variety of transformed cells. It is also detectable in many proliferating non-transformed cells, but it is undetectable or present at low levels in resting cells. It is frequently mutated or inactivated in many types of cancer. p53 seems to act as a tumour suppressor in some, but probably not all, tumour types. p53 has been implicated in cell cycle regulation, particularly in the monitoring of genomic DNA integrity prior to replication; for this reason it has been dubbed 'guardian of the genome'. p53 can be divided into different functional domains: an N-terminal transactivation domain (

), a proline-rich domain, a DNA-binding domain (

) which contains a conserved site (

), a tetramerisation domain (

) and a C-terminal regulatory region.

This entry represents the C-terminal domain of Drosophila transcription factor p53. While the rest of the protein is quite conserved between the different transcription factors such as p53 and p73, the C-terminal domain is highly divergent. The Drosophila p53 structure is characterised by an additional N-terminal β-strand and a C-terminal helix .
Pab87 octamerisation domain superfamily (Pab87_oct_sf)
Type: Homologous_superfamily

This domain was first characterised as the C-terminal domain of Pab87 serine protease from Pyrococcus abyssi . The domain is reported to play a crucial role in Pab87 octamerisation and active site compartmentalisation. Its up-and-down 8-stranded β-barrel 3D structure is reminiscent of the one found in lipocalins.
FlgT, C-terminal domain superfamily (FlgT_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain of a family of flagellar (FlgT) proteins that make up part of the basal body of the flagellum. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT-C is made up of seven β-strands and a helical segment, arranged in a core β-barrel structure and a β-hairpin. The C-terminal domain of FlgT is not essential but stabilises the H-ring structure .
Polyprotein cleavage domain PL2pro superfamily, betacoronavirus (NSP3_PL2pro_sf_bCoV)
Type: Homologous_superfamily

This superfamily represents a domain found in SARS and bat coronaviruses, which is about 70 amino acids in length. PL2pro is a domain of the non-structural protein NSP3, found associated with various other coronavirus proteins due to the polyprotein nature of most viral translation. The domain performs three of the cleavages required to separate the translated polyprotein into its distinct proteins .
SSRP1 domain superfamily (SSRP1_sf)
Type: Homologous_superfamily

This is the dimerization domain found in structure-specific recognition protein SSRP1 (POB3 in yeast) and related proteins, which are components of the FACT complex - a general chromatin factor that acts to reorganise nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair . During transcription elongation the FACT complex acts as a histone chaperone that both destabilises and restores nucleosomal structure .

This domain has a Pleckstrin homology fold, made of 6 β-strands.
Transcription factor DP, C-terminal domain superfamily (TF_DP_C_sf)
Type: Homologous_superfamily

The transcription factor DP (dimerization partner) forms a heterodimer with E2F and regulates genes involved in cell cycle progression. The transcriptional activity of E2F is inhibited by the retinoblastoma protein which binds to the E2F-DP heterodimer and negatively regulates the G1-S transition.
DC-UbP/UBTD2, N-terminal domain superfamily (DC-UbP/UBTD2_N_sf)
Type: Homologous_superfamily

This superfamily represents a ubiquitin-binding domain found in DC-UbP/UBTD2 and consists of three α helices and two small β strands .
NS5A domain 1a superfamily (NS5A_1a_sf)
Type: Homologous_superfamily

The exact function of the Hepatitis C non-structural 5A (NS5A) protein is not known, but it is an active component of the replicase, regulates replication and modulates a range of cellular processes including innate immunity and dysregulated cell growth. NS5A is organised into three domains, labelled I, II and III. Domain I contains a zinc-binding motif and an amphipathic N-terminal helix which promotes membrane association. Mutations disrupting either the membrane anchor or zinc binding are lethal for RNA replication .

This entry represents the 1a domain of NS5A. It binds zinc, which is thought to be crucial for fold maintenance and is essential for replicase function .
Peptidase M64, N-terminal domain superfamily (M64_N_sf)
Type: Homologous_superfamily

This domain is found at the N terminus of IgA Peptidase M64, a family of highly selective metallo-endopeptidases, in this case for IgA, the major class of immunoglobulin in human mucosal secretions. This protein is produced by Clostridium ramosum, a member of the normal flora in the human intestine which is very rarely associated with disease. It has been suggested that this peptidases enable these bacteria to escape specific immune defence on mucosal surfaces . Its function is unknown.
Herpesvirus glycoprotein H, C-terminal domain superfamily (Herpes_glycoH_C_sf)
Type: Homologous_superfamily

Herpesvirus glycoprotein H (gH) is a virion associated envelope glycoprotein . Complex formation between gH and gL has been demonstrated in both virions and infected cells . This superfamily represents the C-terminal domain.

Structurally, the C-terminal domain consists of 8 β-sheets and 1 small α-helix. The β-sheets are arranged into a β-sandwich, made up of two opposed β-sheets, each made up of four strands. Within Herpesvirus glycoprotein H, the two sheets are termed the N sheet and C sheet, since they are sequential. The α-helix sits in the loop between two of the β-strands, and packs against the C sheet.
Transcription factor COE, DNA-binding domain superfamily (COE_DBD_sf)
Type: Homologous_superfamily

This entry represents the DNA-binding domain of COE1, COE2, COE3 and COE4 (also known as Ebf1, Ebf2, Ebf3 and Ebf4), they belong to the early B cell factor family. COE1 is a key transcriptional determinant of B-lymphocyte differentiation . COE3 is a transcription factor involved in neuronal differentiation and maturation .

Structurally, this domain consists of 4 α-helices and 9 β-strands, where the β-strands are arranged into a 9-membered antiparallel barrel.
Streptococcal pilin isopeptide linker superfamily (Strep_pil_link_sf)
Type: Homologous_superfamily

This entry describes a domain that occurs once in the major pilin of Streptococcus pyogenes, Spy0128, but in higher copy numbers in other streptococcal and related bacteria proteins. The domain occurs nine times in a surface-anchored protein of Bifidobacterium longum. All members of this family have LPXTG-type sortase target sequences. The Streptococcus pyogenes major pilin has been shown to undergo isopeptide bond cross-linking, mediated by sortases, that are critical to maintaining pilus structural integrity. One such Lys-to-Asn isopeptide bond is to a near-invariant Asn near the C-terminal end of this domain. A Glu in the S. pyogenes major pilin, invariant as Glu or Gln, is described as catalytic for isopeptide bond formation .
CBM21 domain superfamily (CBM21_dom_sf)
Type: Homologous_superfamily

The carbohydrate binding type-21 or CBM21 domain is a 90-130 amino acid carbohydrate binding domain. The domain is named after proteins classified in carbohydrate-binding module (CBM) family 21 and is sometimes called starch-binding domain (SBD) . The CBM21 domain occurs in several eukaryotic proteins implicated in glycogen metabolism. A glucoamylase active site region or alpha amylase catalytic domain can occur C-terminal to the CBM21 domain. The CBM21 domain of Rhizopus oryzae glucoamylase can bind to raw starch. Most conserved residues are located in a region with a length of 35 in the N-terminal part and in a 15-25 residue motif II at the C terminus of the domain .
Fragilysin, N-terminal domain superfamily (Fragilysin_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of fragilysin, which is an extracellular metalloprotease toxin from B. fragilis, an oportunistic pathogen of human gut. This domain inhibits fragilysin and is cleaved in a mature, virulent form .
Inverse autotransporter, beta-domain superfamily (IAT_beta_sf)
Type: Homologous_superfamily

This domain is found in a group of β-barrel porin-like outer membrane proteins from enteropathogenic Gram-negative bacteria. Intimins and invasins are virulence factors produced by pathogenic Gram-negative bacteria. They carry C-terminal extracellular passenger domains that are involved in adhesion to host cells and N-terminal beta domains that are embedded in the outer membrane. This entry represents the β-barrel porin-like domain in the outer membrane that can be found in intimins, invasins and other inverse autotransporters .

Intimin is believed to mediate adherence and it is necessary for the production of attaching and effacing lesions on tissue culture cells . Invasin is a protein that allows enteric bacteria to penetrate cultured mammalian cells . The entry of invasin in the cell is mediated by binding several beta-1 chain integrins .
Kringle superfamily (Kringle_sf)
Type: Homologous_superfamily

Kringles are autonomous structural domains, found throughout the blood clotting and fibrinolytic proteins. Kringle domains are believed to play a role in binding mediators (e.g., membranes, other proteins or phospholipids), and in the regulation of proteolytic activity . Kringle domains are characterised by a triple loop, 3-disulphide bridge structure, whose conformation is defined by a number of hydrogen bonds and small pieces of anti-parallel β-sheet. They are found in a varying number of copies in some plasma proteins including prothrombin and urokinase-type plasminogen activator, which are serine proteases belonging to MEROPS peptidase family S1A.
NigD-like, N-terminal domain superfamily (NigD-like_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal OB domain found in NigD1 (BT_4005) from Bacteroides thetaiotaomicron and related proteins.

NigD1 is a protein encoded adjacent to genes required for biosynthesis and regulation of lipopolysaccharides (LPS) and phospholipids. This protein was shown to be involved in controlling outer membrane vesicles (OMV) production and act as a molecular switch for OMV biogenesis . NigD1 controls, via currently unknown mechanisms, the amount of LPS, proteins, and lipids allocated to OMVs .
FlgT, N-terminal domain superfamily (FlgT_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of FlgT, a flagellar protein that make up part of the basal body of the flagellum. The flagellum is a large macromolecular assembly composed of three major parts: the basal body, the hook, and the filament. The basal body has two unique ring structures, the T ring and the H ring. FlgT is required to form and stabilise both ring structures. FlgT is composed of three domains, the N-terminal domain (FlgT-N), the middle domain (FlgT-M), and the C-terminal domain (FlgT-C). This N-terminal domain contributes to the construction of the H-ring structure, and adopts a two-layer α-β sandwich architecture composed of a four-stranded anti-parallel β-sheet and two α helices .
Novel toxin 21 superfamily (Ntox21_sf)
Type: Homologous_superfamily

This entry represents an RNase toxin found in bacterial polymorphic toxin systems that is proposed to adopt the BECR (Barnase-EndoU-ColicinE5/D-RelE) fold, with two conserved lysine residues and [DS]xDxxxH, RxG[ST] and RxxD motifs. In bacterial polymorphic toxin systems, the toxin is usually exported by the type 2, type 4, type 5 or type 7 secretion system . This is also referred to as the E. cloacae CdiAC and has been shown to target tRNAs .

The CdiAC proteins carry a variety of sequence-diverse C-terminal domains, which represent a collection of distinct toxins . Many CdiA-CT toxins have nuclease activities. In accord with the structural homology, CdiA-CT cleaves 16S rRNA at the same site as colicin E3 and this nuclease activity is responsible for growth inhibition . These toxins are composed of three domains, each responsible for a distinct step in the cell-killing pathway. The central domain binds specific receptors on the surface of susceptible bacteria, the N-terminal domain mediates translocation across the cell envelope, and the C-terminal domain carries the bacteriocidal activity. This modular structure allows for delivery of diverse C-terminal toxins using conserved translocation and receptor-binding domains .
HMD, C-terminal domain superfamily (HMD_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain of H2-forming N5,N10-methylene-tetrahydromethanopterin dehydrogenases (Hmd) . Hmd is an iron-sulphur-cluster-free enzyme that contains an intrinsic CO ligand bound to iron . This domain is found at the C terminus of two distinct subgroups: one has been experimentally characterised as H2-forming N(5),N(10)-methenyltetrahydromethanopterin dehydrogenase (Hmd or HmdI), and the other one contains isozymes that have not been experimentally characterised (HmdII and HmdIII). Because all three isozyme forms are present in each of the corresponding sequenced genomes, it has been suggested that HmdII and HmdIII may not exhibit Hmd activity and may have a different biological function . Based on HmdII binding to aminoacyl-tRNA synthetases and tRNA, a role for HmdII has been proposed as a regulator of protein synthesis that senses intracellular methylene-H4 MPT concentration .
RICH domain superfamily (RICH_sf)
Type: Homologous_superfamily

This superfamily represents a domain about 85 residues in length and very rich in charged residues, hence its name RICH (Rich In CHarged residues). It is found in secreted proteins such as PspC (

), SpsA (

) and IgA FC receptor (

) from Streptococcus agalactiae. This domain could be involved in bacterial adherence or cell wall binding.
CSTF1, dimerization domain superfamily (CSTF1_dimer_sf)
Type: Homologous_superfamily

This entry represents the dimerisation domain found at the N terminus of cleavage stimulation factor subunit 1 (CSTF1) from eukaryotes. This domain allows for homodimerisation such that the functional state of CSTF1 is a heterohexamer. The Cleavage stimulation Factor (CstF) complex is composed of three subunits and is essential for pre-mRNA 3'-end processing. CstF recognises U and G/U-rich cis-acting RNA sequence elements and helps to stabilise the Cleavage and Polyadenylation Specificity Factor (CPSF) at the polyadenylation site as required for productive RNA cleavage .