SII-SWORD/CoKE huggingface dataset:
TRPM, tetramerisation domain superfamily (TRPM_tetra_sf)
Type: Homologous_superfamily

This entry represents a short anti-parallel coiled-coil tetramerisation domain superfamily of the transient receptor potential cation channel subfamily M member proteins 1/3/6/7. It is held together by extensive core packing and interstrand polar interactions. Transient receptor potential (TRP) channels comprise a large family of tetrameric cation-selective ion channels that respond to diverse forms of sensory input. The presence of cytoplasmic domains that direct channel assembly appears to be a feature of many voltage-gated ion channel superfamily members .
Spermidine synthase, tetramerisation domain superfamily (Spermidine_synt_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal tetramerization domain superfamily of spermidine synthase . Spermidine synthase is involved in the first step of the spermidine biosynthesis subpathway that synthesizes spermidine from putrescine.
Satellite virus coat domain superfamily (Satellite_virus_coat_sf)
Type: Homologous_superfamily

This entry represents a coat domain superfamily found in several satellite viruses, including satellite panicum mosaic virus , satellite tobacco mosaic virus , and satellite tobacco necrosis virus. The coat domain of satellite viruses consist of a β-sandwich jelly-roll fold, with usually eight strands making up the two sheets, although some members can have an extra 1-2 strands. The characteristic interaction between the domains of this fold allows the formation of five-fold and pseudo six-fold assemblies. Although the satellite virus coat proteins share the same jelly-roll fold, they differ in the arrangement of their secondary structural elements and in the interactions of adjacent subunits .
Aldehyde oxidase/xanthine dehydrogenase, molybdopterin binding domain superfamily (AldOxase/xan_DH_Mopterin-bd_sf)
Type: Homologous_superfamily

Aldehyde oxidase (AOX

) catalyses the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide. The enzyme is a homodimer, and requires FAD, molybdenum and two 2FE-2S clusters as cofactors. Xanthine dehydrogenase (XDH

) catalyses the hydrogenation of xanthine to urate, and also requires FAD, molybdenum and two 2FE-2S clusters as cofactors. This activity is often found in a bifunctional enzyme with xanthine oxidase (

) activity too. The enzyme can be converted from the dehydrogenase form to the oxidase form irreversibly by proteolysis or reversibly through oxidation of sulfhydryl groups .

The aldehyde oxido-reductase (Mop) from the sulphate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas is a homodimer of 907 amino acid residues subunits and is a member of the xanthine oxidase family. The protein contains a molybdopterin cofactor (Mo-co) and two different [2Fe-2S] centres. It is folded into four domains of which the first two bind the iron sulphur centres and the last two are involved in Mo-co binding. Mo-co is a molybdenum molybdopterin cytosine dinucleotide. Molybdopterin forms a tricyclic system with the pterin bicycle annealed to a pyran ring. The molybdopterin dinucleotide is deeply buried in the protein. The cis-dithiolene group of the pyran ring binds the molybdenum, which is coordinated by three more (oxygen) ligands .

This superfamily represents the molybdopterin binding domain.
D-Ala-D-Ala carboxypeptidase, C-terminal domain superfamily (Peptidase_S11_C_sf)
Type: Homologous_superfamily

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .

This entry contains proteins that are annotated as penicillin-binding protein 5 and 6. These belong to MEROPS peptidase family S11 (D-Ala-D-Ala carboxypeptidase A family, clan SE). Penicillin-binding protein 5 expressed by Escherichia coli functions as a D-alanyl-D-alanine carboxypeptidase. It is composed of two domains that are oriented at approximately right angles to each other. The N-terminal domain (

) is the catalytic domain. The C-terminal domain, this entry, is organised into a sandwich of two anti-parallel β-sheets, and has a relatively hydrophobic surface as compared to the N-terminal domain. Its precise function is unknown; it may mediate interactions with other cell wall-synthesising enzymes, thus allowing the protein to be recruited to areas of active cell wall synthesis. It may also function as a linker domain that positions the active site in the catalytic domain closer to the peptidoglycan layer, to allow it to interact with cell wall peptides .
Virulence factor YopE, GAP domain superfamily (YopE_GAP_dom_sf)
Type: Homologous_superfamily

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Yersinia secrete a Rho GTPase-activating protein, YopE , that disrupts the host cell actin cytoskeleton. YopE is regulated by another bacterial gene, SycE , that enables the exotoxin to remain soluble in the bacterial cytoplasm. A similar protein, exoenzyme S (ExoS) from Pseudomonas aeruginosa, has both ADP-ribosylation and GTPase activity .

This entry represents the bacterial GAP (GTPase-activating protein) domain found in YopE, ExoS, and also SptP (Secreted effector protein) .
Mitochondrial cytochrome c oxidase subunit VIc/VIIs superfamily (Cytochrome_c_oxidase_VIc_sf)
Type: Homologous_superfamily

Cytochrome c oxidase (CcO;

), a 13 subunit complex, is the terminal oxidase in the mitochondrial electron transport chain . This entry contains of cytochrome c oxidase subunit VIc superfamily, which is found only in eukaryotes and its specific function remains unclear. It has been reported that the relative concentrations of some nuclear encoded CcO subunits, including subunit VIc, compared to those of the mitochondrial encoded subunits, are altered significantly during the progression of prostate cancer .

This entry also includes Dictyostelium cytochrome c oxidase VIIs superfamily, an alternative subunit VII isoform produced under hypoxia .
NagB/RpiA transferase-like (NagB/RpiA_transferase-like)
Type: Homologous_superfamily

This entry is composed of multiple transferases, mainly ribose-5-phosphate isomerase A (RpiA), glucosamine-6-phosphate deaminase (NagB) and 6-phosphogluconolactonase (6PGL). RpiA and 6PGL are involved in the pentose phosphate pathway while NagB is involved in the last step of the N-acetylneuraminate degradation pathway. These enzymes share a common core α/β structure .
Flavivirus capsid protein C superfamily (Flavi_capsidC_sf)
Type: Homologous_superfamily

The capsid protein C plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle .

This superfamily represents the Flavivirus capsid protein C. Its core structure is composed of five helices with right-handed superhelix and swapped dimer with the two long C-terminal helices.
Trimeric adhesin (Trimeric_adhesin)
Type: Homologous_superfamily

The trimeric autotransporter adhesins superfamily includes Neisseriahia/hsf homologue (NhhA) and the H. influenzae Hia autotransporter . The structure of trimeric adhesin consists of a trimer which contains two different β-prism-like domains connected by a linker subdomain of less regular structure.
Kynurenine formamidase superfamily (KFase_sf)
Type: Homologous_superfamily

Kynurenine formamidase catalyses the hydrolysis of N-formyl-L-kynurenine to L-kynurenine, the second step in the kynurenine pathway of tryptophan degradation . The proteins contain a conserved motif HXGTHXDXPXH that is likely to form a part of the active site.

Structurally, it contains a mixed β-sheet close barrel fold.
Osmotin/thaumatin-like superfamily (Osmotin/thaumatin-like_sf)
Type: Homologous_superfamily

Thaumatin is an intensely sweet-tasting protein, 100 000 times sweeter than sucrose on a molar basis found in berries from Thaumatococcus daniellii, a tropical flowering plant known as Katemfe. When attacked by viroids, single-stranded unencapsulated RNA molecules that do not code for protein, thaumatin is induced.

Thaumatin consists of about 200 residues and contains 8 disulphide bonds. Like other PR proteins, thaumatin is predicted to have a mainly β structure, with a high content of β-turns and little helix .

Osmotin belongs to the PR-5 protein family whose members are homologous to thaumatin. Osmotin and other PR-5 proteins were shown to have antifungal activity in vitro against a broad range of fungi, including several plant pathogens.
Dynein light chain superfamily (DLC_sf)
Type: Homologous_superfamily

Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Dynein is composed of a number of ATP-binding large subunits (see

), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family . Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex .

Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of β-α(2)-β-X-β(2) .
Colicin D, C-terminal domain superfamily (ColicinD_C_sf)
Type: Homologous_superfamily

Colicin D is a bacteriocin that kills target cells by cleaving tRNA(Arg). This entry represents a domain found in the C terminus of colicin D, which is responsible for its catalytic activity . The domain is also found in some S-type pyocins, which are also bacteriocins.

Structurally, the C-terminal domain of colicin D is composed of an α(2)-β(4)-α fold arranged in two layers (α/β) with antiparallel β sheet.
Nucleocapsid protein, C-terminal (Nucleocapsid_C)
Type: Homologous_superfamily

The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 .

Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains . Both domains contribute to the binding of viral RNA genome .

This entry represents the C-terminal domain of the nucleocapsid proteins from Coronavirus and Arterivirus. The C-terminal domain of the N protein (N-CTD) is involved in dimerization, and is thus, also called the dimerization domain . Structurally, the C-terminal domain forms a tightly intertwined dimer with an intermolecular four-stranded central β-sheet platform flanked by α helices, indicating that the basic building block for coronavirus nucleocapsid formation is a dimeric assembly of N protein .
Hypothetical protein HI1480 (HI1480)
Type: Homologous_superfamily

This entry contains a protein of unknown function, the hypothetical protein HI1480 from Haemophilus influenzae. Its structure has been determined (

) and consists of a β-α(4)-β-α-β fold with segregated α-helical and β-sheet subdomains and a dimeric β-sheet barrel, the helical region contains a four-helix bundle .
Suppressor of fused, N-terminal (SUFU_N)
Type: Homologous_superfamily

Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling . It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade , and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway . Homologues of Sufu have been found in bacteria, though their function is not currently known.

Sufu contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1 . This entry represents the N-terminal domain of Sufu. Its structure has an unusual fold composed of bifurcated β-sheet with left-handed β-α-β unit.
Multidrug transporter EmrE superfamily (EmrE-like)
Type: Homologous_superfamily

This superfamily, with a founding member EmrE, represents a number of membrane transporters some of which involved in multidrug resistance. Members contain four non-compact transmembrane helices that can oligomerise.

EmrE, a multidrug transporter from Escherichia coli, functions as a homodimer of a small four-transmembrane protein. It confers resistance to a wide range of toxic compounds, including ethidium, methyl viologen, acriflavine, tetraphenylphosphonium (TPP+), benzalkonium, propidium, dequalinium and the aminoglycoside antibiotics streptomycin and tobramycin .

The Undecaprenyl phosphate-aminoarabinose (also known as 4-amino-4-deoxy-L-arabinose-phosphoundecaprenol) flippase subunit ArnE translocates 4-amino-4-deoxy-L-arabinose-phosphoundecaprenol from the cytoplasmic to the periplasmic side of the inner membrane and is involved in the lipopolysaccharide biosynthesis.
Minicollagen I, C-terminal domain (Minicollagen_I_C)
Type: Homologous_superfamily

Minicollagen-1 from the nematocysts of Hydra is a trimeric protein that contains cysteine-rich domains at the N and C termini, which are involved in the assembly of an intermolecular disulfide network .

The C-terminal minicollagen cysteine rich domain of Hydra consists of only 24 amino acids, six of which are prolines and six are cysteines bonded in disulfide bridges that constrain the structure into a new fold . The minicollagen cysteine-rich domains are believed to function in a switch of the disulfide connectivity from intra to intermolecular bonds during maturation of the capsule wall .
DksA, N-terminal domain superfamily (DnaK_N)
Type: Homologous_superfamily

DksA (DnaK suppressor A) is originally named as a multicopy suppressor of temperature sensitivity of dnaKJ mutants . DksA is a transcription factor that acts by binding directly to the RNA polymerase (RNAP). It is required for negative regulation of rRNA expression and positive regulation of several amino acid biosynthesis promoters .

The N-terminal domain of DksA consists of two helices arranged in antiparallel α-hairpin with left-handed twist.
Ribosome maturation protein Sdo1/SBDS, central domain superfamily (Sdo1/SBDS_central_sf)
Type: Homologous_superfamily

Proteins containing this domain are highly conserved in species ranging from archaea to vertebrates and plants , including several Shwachman-Bodian-Diamond syndrome (SBDS, OMIM 260400) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition. Members of this superfamily play a role in RNA metabolism . In yeast Sdo1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition .

The SBDS protein is composed of three domains. The N-terminal (FYSH) domain is the most frequent target for disease mutations and contains a novel mixed α/β-fold, the central domain, represented in this entry, consists of a three-helical bundle and the C-terminal domain has a ferredoxin-like fold .
HBS1-like protein, N-terminal domain superfamily (HBS1-like_N_sf)
Type: Homologous_superfamily

This domain is found at the N terminus of HBS1 proteins. It interacts with the ribosomal protein rpS3 at the mRNA entry site .
LIS1, N-terminal (LIS1_N)
Type: Homologous_superfamily

This entry represents the N-terminal domain of Lissencephaly-1 (LIS1). LIS1 is required for nuclear migration in fungi, cell cycle progression in mammals, and the formation of a folded cerebral cortex in humans. They appear to regulate the mechanical behaviour of cytoplasmic dynein, the primary minus-end-directed microtubule motor . Proteins containing this domain include:

Platelet-activating factor acetylhydrolase IB subunit alpha, also known as Lissencephaly-1 protein .

Nuclear distribution protein PAC1 from budding yeasts .

Fungal nuclear distribution protein nudF .

Mutations in the LIS1 gene cause Lissencephaly-1, a classical lissencephaly characterised by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex .
VPS9 domain superfamily (VPS9_dom_sf)
Type: Homologous_superfamily

Rab proteins form a family of signal-transducing GTPases that cycle between active GTP-bound and inactive GDP-bound forms. The Rab5 GTPase is an essential regulator of endocytosis and endosome biogenesis. Rab5 is activated by GDP-GTP exchange factors (GEFs) that contain a VPS9 domain and generate the Rab5-GTP complex . The VPS9 domain catalyses nucleotide exchange on Rab5 or the yeast homologue VPS21 . The domain has a length of ~140 residues and forms the central part of the yeast VPS9 (vacuolar protein sorting-associated) protein, which acts as a GEF for VPS21. Some domains which can occur in combination with the VPS9 domain are CUE, A20-type zinc finger, Ras-associating (RA), SH2, RCC1, DH, PH, rasGAP, MORN and ankyrin repeat.

Structurally, the VPS9 domain adopts a layered fold of six α helices. Conserved residues from the fourth and sixth helices and the
loops N-terminal to these helices form the surface that interacts with Rab5
and Rab21 .
ERO1-like superfamily (ERO1-like_sf)
Type: Homologous_superfamily

Ero1 and PDI form the disulfide relay system of the ER that supports correct disulfide bond formation of secretory proteins. This entry represents Ero1 (endoplasmic oxidoreductin-1) from yeasts and its homologues from mammals, Ero1-alpha and Ero1-beta. Ero1 is an flavoprotein that directly transfers disulfide bonds to disulfide isomerase PDI . Ero1 acts as an thiol oxidoreductase responsible for catalyzing disulfide bond formation in nascent polypeptide substrates via electron transfer through protein disulfide isomerase (PDI) with oxygen acting as the final electron acceptor . Newly generated disulfides are transferred from a FAD (flavin adenine dinucleotide)-associated active site via a "shuttle disulfide" cysteine pair in Ero1 to PDI and from there on to substrate proteins . The activity of Ero1 is regulated by PDI (also known as Pdi1). This regulation of Ero1 through reduction and oxidation of regulatory bonds within Ero1 is essential for maintaining the proper redox balance in the ER .

ERO1 has a multihelical structure consisting of two four-helical bundles.
GDNF receptor alpha (GDNF_alpha)
Type: Homologous_superfamily

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) receptors are potent survival factors for sympathetic, sensory and central nervous system neurons . GDNF and neurturin promote neuronal survival by signalling through similar multicomponent receptors that consist of a common receptor tyrosine kinase and a member of a GPI-linked family of receptors that determines ligand specificity .

Structurally, GDNF is composed of five helices with an irregular disulfide-linked array. It is topologically similar to the fungal elicitin fold (

).
NS2, N-terminal (NS2_N)
Type: Homologous_superfamily

The non-structural protein 2 (NS2) is a non-specific single-stranded RNA-binding protein that forms large homomultimers and accumulates in viral inclusion bodies of infected cells. Three RNA-binding regions have been identified in Bluetongue virus 17 (

) at residues 2-11, 153-166 and 274-286 . NS2 multimers also possess nucleotidyl phosphatase activity . The precise function of NS2 is not known, but it may be involved in the transport and condensation of viral mRNAs .

This entry represents the N-terminal domain of NS2. It contains a β sandwich structure composed of nine strands arranged in two sheets with unusual topology with two crossover loops.