SII-SWORD/CoKE huggingface dataset:
Vesicle transport v-SNARE, N-terminal domain superfamily (v-SNARE_N_sf)
Type: Homologous_superfamily

v-SNARE proteins are required for protein traffic between eukaryotic organelles. The v-SNAREs on transport vesicles interact with t-SNAREs on target membranes in order to facilitate this . This domain is the N-terminal half of the v-Snare proteins.
Gnk2-homologous domain superfamily (GNK2_sf)
Type: Homologous_superfamily

Ginkbilobin-2 (Gnk2) is an antifungal protein found in the endosperm of Ginkgo seeds, which inhibits the growth of phytopathogenic fungi such as Fusarium oxysporum. Gnk2 has considerable homology (~85%) to embryo-abundant proteins (EAP) from the gymnosperms Picea abies and P. glauca. Plant EAP are expressed in the late stage of seed maturation and are involved in protection against environmental stresses such as drought. The sequence of Gnk2 is also 28-31% identical to the extracellular domain of cysteine-rich receptor-like kinases (CRK) from the angiosperm Arabidopsis. The CRK members are induced by pathogen infection and treatment with reactive oxygen species or salicylic acid and are involved in the hypersensitive reaction, which is a typical system of programmed cell death. In addition, there are at least 60 genes in Arabidopsis encoding the cysteine-rich secreted proteins (CRSP) with an Gnk2-homologous domain. Therefore, the proteins with a Gnk2-homologous domain are regarded as one of the largest protein superfamilies, although the role of the conserved Gnk2-homologous domain remains unclear . The Gnk2-homologous domain is composed of two α-helices and a five stranded β-sheet, which forms a compact single-domain architecture with an α+β-fold. It contains a C-X(8)-C-X(2)-C motif. Cysteine residues form three intramolecular disulphide bridges: C1-C5, C2-C3, and C4-C6 .
Ycf54-like superfamily (Ycf54-like_sf)
Type: Homologous_superfamily

Ycf54 is found encoded in the chloroplast genomes of algae, it is also found in plants and in the cyanobacteria. Ycf54 is a component of the MgPME-cyclase complex. Ycf54 plays two roles in the function of the MgPME-cyclase. First, it plays a critical role in t assembly/stability of the Mg-cyclase complex and its constituents and, secondly, is required for normal Pchlide formation. Both functions indicate that this protein is required for optimal MgPME-cyclase activity, although it is not absolutely essential .
GxGYxYP putative glycoside hydrolase, C-terminal domain superfamily (GxGYxYP_C_sf)
Type: Homologous_superfamily

This domain can be found in the C-terminal region of a group of putative glycoside hydrolases. This domain contains a characteristic sequence motif, GxGYxYP.
PurL, C-terminal domain superfamily (PurL_C_sf)
Type: Homologous_superfamily

This is the C-terminal subdomain of the FGAM (formylglycinamidine ribonucleotide) synthetase domain found in PurL (also known as phosphoribosylformylglycinamidine synthase subunit II) from Thermatoga and related species. PurL catalyses the ATP-dependent synthesis of formylglycinamidine ribonucleotide (FGAM) from formylglycinamide ribonucleotide (FGAR) and glutamine, the fourth step of the purine biosynthetic pathway .

Two forms of PurL have been characterised, large and small. Large PurL is present in most Gram-negative bacteria and eukaryotes and consists of a single polypeptide chain comprised of an N-terminal domain, an FGAM synthetase domain, and a glutaminase domain, with a putative ammonia channel located between the active sites of the latter two. Small PurL, present in Gram-positive bacteria and archaea, is structurally homologous to the FGAM synthetase domain of large PurL, and forms a complex with two additional gene products, PurQ and PurS .

The FGAM synthetase domain is divided into four subdomains: A1 and A2 which make up the core of the enzyme and B1 and B2, which represent the N-terminal and C-terminal subdomains, respectively .
Pepsin inhibitor-3 domain superfamily (Pepsin-I3_sf)
Type: Homologous_superfamily

Pepsin inhibitor-3 consists of two tandem repeat domains, each comprising an antiparallel β-sheet flanked by an α-helix. In the enzyme-inhibitor complex, the N-terminal β-strand of PI-3 pairs with one strand of the active site flap region of pepsin .
FTO, C-terminal domain superfamily (FTO_C_sf)
Type: Homologous_superfamily

FTO contains two well-defined domains: an N- (residues 32-326) and a C- (residues 327-498) terminal domain. The N-terminal domain of this protein is a DNA demethylase . This entry represents the C-terminal domain (CTD). This domain is α-helical with α7, α8 and α10 forming a three-helix bundle. One end of the helix bundle interacts with the N-terminal domain of FTO, and it has been suggested that the CTD plays a role in stabilising the NTD's conformation since the NTD only exhibits enzymatic activity when co-expressed with the CTD .

Alpha-ketoglutarate-dependent dioxygenase FTO, also known as Fat mass and obesity-associated protein, is a nucleus protein which belongs to the FTO family. This enzyme is a dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation . FTO activity is highest towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. FTO has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine ,

]. FTO has no activity towards 1-methylguanine. It has no detectable activity towards double-stranded DNA. FTO requires molecular oxygen, alpha-ketoglutarate and iron. FTO contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. It contributes to the regulation of body size and body fat accumulation as well .
Cbb3-type cytochrome c oxidase subunit CcoP, N-terminal domain superfamily (CcoP_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of Cbb3-type cytochrome c oxidase subunit CcoP . CcoP subunit is required for transferring electrons from donor cytochrome c via its heme groups to CcoO subunit.
Minor type IV pilin, PilX-like superfamily (Pilin_PilX-like_sf)
Type: Homologous_superfamily

PilX is a protein from Neissaria meningitidis which is crucial for the formation of bacterial aggregates and adhesion to human cells . The structure of PilX is similar to all pilins as it has the common α/β roll fold. PilX subunits have surface-exposed motifs which are thought to stabilise bacterial aggregates against pilus retraction. It also illustrates how a minor pilus component can modulate the virulence properties of pili which have a simple composition and structure .
Sigma 54 modulation/S30EA ribosomal protein, C-terminal domain superfamily (Ribosom_S30AE_C_sf)
Type: Homologous_superfamily

This domain often occurs at the C terminus of the ribosomal protein S30Ae/sigma 54 modulation protein (

).
Alpha-galactosidase, N-terminal domain superfamily (Alpga-gal_N_sf)
Type: Homologous_superfamily

This domain is found at the N terminus of many alpha-galactosidases (Aga), members of the glycoside hydrolase family 36. The Aga protomer is compact and folds into three domains: N-terminal, catalytic, and C-terminal domains. The N-terminal domain presents a β-supersandwich fold with 20 β-strands and four antiparallel β-sheets .
6-pyruvoyl tetrahydropterin synthase/QueD superfamily (6-PTP_synth/QueD_sf)
Type: Homologous_superfamily

6-Pyruvoyl tetrahydrobiopterin synthase (PTPS) catalyses the conversion of dihydroneopterin triphosphate to 6-pyruvoyl tetrahydropterin, the second of three enzymatic steps in the synthesis of tetrahydrobiopterin from GTP . The functional enzyme is a hexamer of identical subunits. A transition metal binding site formed by the three histidine residues 23, 48 and 50 is present in each subunit, and bound Zn(II) is responsible for the enzymatic activity. Site-directed mutagenesis of each of these three histidine residues results in a complete loss of metal binding and enzymatic activity .

Member this entry is also 6-carboxy-5,6,7,8-tetrahydropterin synthase (QueD) that catalyses the conversion of 7,8-dihydroneopterin triphosphate (H2NTP) to 6-carboxy-5,6,7,8-tetrahydropterin (CPH4) and acetaldehyde .
Poly(A) polymerase, nucleotidyltransferase domain superfamily, Poxvirus (PolyA_pol_nucTrfase_sf_Poxvir)
Type: Homologous_superfamily

Poly(A) polymerase (

) catalyses template-independent extension of the 3'-end of a DNA or RNA strand by one nucleotide at a time. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer of a catalytic and a regulatory subunit. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer composed of a catalytic (VP55, also known as PAP-L) and a regulatory subunit (VP39). VP55 comprises three domains: the N-terminal or N domain, the central or catalytic domain, and the C-terminal or C domain, all three domains having distinct topologies. The core comprises a mixed nine-stranded twisted β sheet, with the first seven strands being folded from one long (118 residue) polypeptide segment that follows the N domain and the last two strands originating from the extreme C-terminal-most 15 residues of the entire polypeptide chain. Of the four α-helices in the catalytic domain, the two longest (J and L) near the surface pack against one side of the β-sheet in a nearly parallel orientation to the β-strands .

This entry represents the nucleotidyltransferase (central) domain of the catalytic subunit VP55 .
PapG, carbohydrate-binding domain superfamily (PapG_carbohydrate-bd_sf)
Type: Homologous_superfamily

PapG, the adhesin of the P-pili, is situated at the tip and is only a minor component of the whole pilus structure. A two-domain structure has been postulated for PapG; a carbohydrate binding N terminus (this domain) and chaperone binding C terminus. The carbohydrate-binding domain interacts with the receptor glycan .
Sensor histidine kinase RisS, periplasmic domain superfamily (RisS_PPD_sf)
Type: Homologous_superfamily

This entry represents the periplasmic domain of the sensor histidine kinases such as RisS. It is purported to be the region of the kinase that senses the pH of the environs.
Cut8/Sts1 superfamily (Cut8/Sts1_sf)
Type: Homologous_superfamily

This entry includes fission yeast tethering factor for nuclear proteasome Cut8 protein and its homologue, Sts1.
Calcium-dependent cell adhesion molecule, C-terminal domain superfamily (CAD_C_sf)
Type: Homologous_superfamily

This domain is found at the C terminus of Dictyostelium discoideum Calcium-dependent cell adhesion molecule, which has an immunoglobulin-like fold . It tethers the protein to the cell membrane. Calcium-dependent cell adhesion molecule 1 mediates calcium-dependent cell-cell adhesion during the early stage of development .
Histidine kinase PdtaS, GAF domain superfamily (H_kinase_PdtaS_GAF_sf)
Type: Homologous_superfamily

This entry represents the GAF domain of the sensor region in the cytosolic histidine kinase (HK), PdtaS, from Mycobacterium tuberculosis. The N-terminal region of this protein is comprised of closely linked GAF and PAS domains, both are ubiquitous and form dimeric interfaces. GAF domains are known to bind heme (as can PAS domains), to be involved in redox responses and even to function as catalytic domains .

PdtaS is a member of the two-component regulatory system PdtaR/PdtaS , which plays an essential role in mycobacterial adaptation to poor nutrient conditions. Under nutrient deprivation, there is an increase of intracellular concentrations of c-di-GMP which binds to the PdtaS sensor and promotes its autophosphorylation, leading to the activation of the signaling cascade .
GAT domain superfamily (GAT_sf)
Type: Homologous_superfamily

The GAT domain is a region of homology of ~130 residues, which is found in eukaryotic GGAs (for Golgi-localized, gamma ear-containing ADP ribosylation factor (ARF)-binding proteins) and vertebrate TOMs (for target of myb). The GAT domain is found in its entirety only in GGAs, although, at the C terminus it shares partial sequence similarity with a short region of TOMs. The GAT domain is found in association with other domains, such as VHS and GAE. The GAT domain of GGAs serves as a molecular anchor of GGA to trans-Golgi network (TGN) membranes via its interaction with the GTP-bound form of a member of the ARF family of small GTPases and can bind specifically to the Rab GTPase effector rabaptin5 and to ubiquitin .

The GGA-GAT domain possesses an all α-helical structure, composed of four helices arranged in a somewhat unusual topology, which has been called the helical paper clip. The overall structure shows that the GAT domain has an elongated shape, in which the longest helix participates in two small independent subdomains: an N-terminal helix-loop-helix hook and a C-terminal three-helix bundle. The hook subdomain has been shown to be both necessary and sufficient for ARF-GTP binding and Golgi targeting of GGAs. The N-terminal hook subdomain contains a hydrophobic patch, which is found to interact directly with ARF . It has been proposed that this interaction might stabilise the hook subdomain . The C-terminal three-helix bundle is involved in the binding with Rabaptin5 and ubiquitin .
Vacuolar R-SNARE Nyv1, longin domain superfamily (Nyv1_longin_sf)
Type: Homologous_superfamily

SNARE-mediated fusion typically results in the formation a complex consisting of three Q-SNAREs and one R-SNARE. R-SNAREs that contain a profilin-like fold in their N-terminal domains have been termed longins. The genome of the yeast Saccharomyces cerevisiae encodes five R-SNAREs of which three (Sec22, Ykt6, and Nyv1) have the longin domain. It is important to note that the given longin domain (LD) is not restricted to R-SNAREs and has been identified in a variety of proteins .

This entry represents the N-terminal longin domain of Nyv1. This domain contains a YXXomega-like sorting motif (Y31GTI34), which is responsible for the AP3-dependent vacuolar localization of Nyv1 .
Two-component histidine kinase, sensor domain superfamily (HK_sensor_dom_sf)
Type: Homologous_superfamily

This entry represents the sensor domain found at the N terminus of integral membrane two-component system sensor histidine kinases, such as PfeS from Pseudomonas aeruginosa .
PhoQ Sensor superfamily (PhoQ_Sensor_sf)
Type: Homologous_superfamily

The PhoQ Sensor is required for the virulence of various Gram-negative bacteria by allowing interaction of PhoPQ with the intracellular membrane, resulting in remodelling of the bacterial cell surface and subsequent bacterial resistance to host antimicrobial peptides. The domain contains a major flat acidic surface, which binds to at least 3 calcium ions, neutralising the domain's negative charge and allowing interaction with the negatively charged membrane . This domain recognises divalent metal cations and antimicrobial cationic peptides (Matilla et. el., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
NADH:ubiquinone oxidoreductase, subunit 3 superfamily (NDAH_ubi_oxred_su3_sf)
Type: Homologous_superfamily

This superfamily contains the subunit 3 of the NADH-ubiquinone oxidoreductase and the subunit A of the NADH-quinone oxidoreductase.
Killer toxin SMK, beta subunit superfamily (Killer_tox_SMK_b_sf)
Type: Homologous_superfamily

The killer toxin SMK (salt-mediated killer) from the halotolerant yeast Pichia farinosa acts to kill sensitive strains of yeast. SMK exhibits maximum activity under conditions of acidic pH and high salt concentration. It is composed of two distinct subunits, alpha and beta, which tightly interact with each other under acidic conditions, jointly folding into an ellipsoidal single domain structure belonging to the α/β-sandwich family. SMK assumes a similar folding topology to the fungal killer toxin KP4, forming two left-handed split β/α/β motifs, which is rarely found in other toxins; hence, these toxins may be evolutionarily or functionally related . SMK appears to function by associating with the membranes of sensitive cells .
PulS/OutS-like superfamily (PulS/OutS-like_sf)
Type: Homologous_superfamily

This superfamily comprises lipoproteins from gammaproteobacterial species: pullulanase secretion protein PulS protein of Klebsiella pneumoniae (

), the lipoprotein OutS protein of Erwinia chrysanthemi (

) and the functionally uncharacterised type II secretion protein EtpO (

) from Escherichia coli O157:H7. PulS and OutS have been shown to interact with and facilitate insertion of secretins into the outer membrane, suggesting a chaperone-like, or piloting function for members of this superfamily. These proteins consist of 4 α helices arranged into a slightly elongated, C-shaped helical bundle. Within PulS, the helices form a binding groove which interact with a disordered region on another protein, PulD, to form a PulS-PulD complex. PulD then oligomerises into a dodecameric outer membrane complex in the formation of a type II secretion system .

In addition to the PulS/OutS proteins this entry also includes other functionally uncharacterised proteins, such as YacC from Escherischia coli (

).
YARHG domain superfamily (YARHG_sf)
Type: Homologous_superfamily

This presumed extracellular domain is about 70 amino acids in length. It is named YARHG after a conserved motif in the sequence. This domain is associated with peptidases and bacterial kinase proteins. Its molecular function is unknown.
Probable DNA packing protein, C-terminal domain superfamily (DNA_pack_C_sf)
Type: Homologous_superfamily

This superfamily includes proteins that are probably involved in DNA packing in Herpesviridae. This domain is found at the C terminus of the protein.
Effector protein NleG superfamily (Effector_NleG_sf)
Type: Homologous_superfamily

Many bacterial pathogens deliver effector proteins into host cells via a type III secretion system, enabling them to manipulate host cell biology in ways that benefit the pathogen. In enterohaemorrhagic Escherichia coli O157:H7, the NleG protein and its homologues represent the largest family of effector proteins, with 14 members identified in the Sakai strain alone . Members of the NleG family share a conserved C-terminal domain that adopts a structure similar to the RING finger/U-box domain found in eukaryotic ubiquitin ligases . These domains allow NleG proteins to selectively interact with human E2 ubiquitin-conjugating enzymes and exhibit in vitro activity characteristic of eukaryotic E3 ligases, although the precise role of this activity in pathogenesis remains unclear. Effector proteins such as NleG are believed to alter host cell physiology and promote bacterial survival within host tissues. This particular protein is likely an E3 ubiquitin-protein ligase that interferes with the host ubiquitination pathway, directing host proteins towards proteasomal degradation. Supporting its role in virulence, mice infected with a bacterial strain lacking this gene display less severe diarrhoea .
GINS complex, subunit Psf3 superfamily (GINS_Psf3_sf)
Type: Homologous_superfamily

DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.

A novel replication complex, GINS (for Go, Ichi, Nii, and San; meaning 5-1-2-3 in Japanese, after the four related subunits of the complex Sld5, Psf1, Psf2 and Psf3), has been identified . The GINS complex is conserved in eukaryotic cells and is essential for DNA replication. When the DNA replication fork is opened, GINS is required to maintain the association between the MCM and Cdc45 in the large replicator complex . The GINS complex acts as a replicative helicase that unlocks the double-stranded DNA prior to the moving replication fork .

Psf2's expression is up regulated in many diseases, especially tumors, and adversely affects prognosis .

The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts . This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes. This superfamily represents the Psf3 component.

Electron microscopy of GINS shows that it forms a ring-like structure , reminiscent of the structure of PCNA , the DNA polymerase delta replication clamp. The eukaryotic GINS subunits are homologous. The four subunits of the complex consist of two domains each, termed the α-helical (A) and β-strand (B) domains. The A and B domains of Sld5/Psf1 are permuted with respect to Psf1/Psf3 .
Alanyl aminopeptidase, Ig-like domain superfamily (PepN_Ig-like_sf)
Type: Homologous_superfamily

This entry represents a conserved domain with an Ig-like fold found in a group of zinc metallopeptidases the belong to MEROPS peptidase family M1 (aminopeptidase N, clan MA); the majority are identified as alanyl aminopeptidases (proteobacteria) that are closely related to E. coli PepN and presumed to have a similar (not identical) function. Nearly all are found in proteobacteria, but members are found also in cyanobacteria, plants, and apicomplexan parasites . This group differs greatly in sequence from the family of aminopeptidases typified by Streptomyces lividans PepN (

) and from the membrane bound aminopeptidase N family in animals.
FimV, C-terminal domain superfamily (FimV_C_sf)
Type: Homologous_superfamily

This superfamily represents a domain found at the extreme C terminus of the Mobility protein FimV from Pseudomonas aeruginosa, and of TspA of Neisseria meningitidis . Disruption of the former blocks twitching motility from type IV pili, which suggests a role in peptidoglycan layer remodeling required by type IV fimbrial systems .
THAP-type zinc finger superfamily (THAP_Znf_sf)
Type: Homologous_superfamily

The THAP-type zinc finger (consensus: C-x(2,4)-C-x(35,50)-C-x(2)-H) is an ~90-residue domain restricted to animals, which is shared between the THAP family of cellular DNA-binding proteins, and transposases from mobile genomic parasites . THAP1, the prototype of the THAP family, possesses zinc-dependent sequence-specific DNA binding activity and recognizes a consensus DNA target sequence of 11 nucleotides . The THAP-type zinc finger can be found in one or more copies and can be associated with other domains, such as the C2H2-type zinc finger.

The structure of the THAP-type zinc finger reveals the presence between the C2CH zinc coordinating residues of a short antiparallel β-sheet interspersed by a long loop-helix-loop insertion. This loop-helix-loop motif has been shown to be essential for the identification of a number of critical residues for DNA recognition .
Dsl1, N-terminal domain superfamily (Dsl1_N_sf)
Type: Homologous_superfamily

Dsl1 is a peripheral membrane protein, part of the DSL1 complex, required for transport between the Golgi and the endoplasmic reticulum . It is localised to the ER membrane, and bridges the other two subunits of the complex, Tip20 and Sec39. DSL1 complex, together with conserved oligomeric Golgi (COG), Golgi-associated retrograde protein (GARP), and the exocyst, is a member of the complexes associated with tethering containing helical rods (CATCHR) family, which are evolutionary related and share structural features . This complex interacts at its base with ER SNAREs and at its tip with COPI vesicles, thus, it captures Golgi-derived COP-I vesicles and facilitates their fusion with the ER the Dsl1 complex, upstream of SNARE complex formation . The C-terminal domain is involved in binding to the Sec39 subunit of the Dsl1p complex . The N-terminal complexes with another subunit of the Dsl1p complex called Tip20 which forms heterodimers by pairing the N termini of each protein .