SII-SWORD/CoKE huggingface dataset:
Flaviviral glycoprotein E, dimerisation domain (Glycoprot_E_dimer_dom)
Type: Homologous_superfamily

Flaviviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Yellow fever virus (YFV), West Nile virus (WNV), Tick-borne encephalitis virus, Japanese encephalitis virus (JE) and Dengue virus 2 viruses . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C (IPR001122), and the envelope glycoproteins M (IPR000069) and E. Glycoprotein E is a class II viral fusion protein that mediates both receptor binding and fusion. Class II viral fusion proteins are found in flaviviruses and alphaviruses, and are structurally distinct from class I fusion proteins from influenza virus and HIV.

Glycoprotein E is comprised of three domains: domain I (dimerisation domain) is an 8-stranded β barrel, domain II (central domain) is an elongated domain composed of twelve β strands and two α helices, and domain III (immunoglobulin-like domain) is an IgC-like module with ten β strands. Domains I and II are intertwined . This superfamily represents domain I.

The glycoprotein E dimers on the viral surface re-cluster irreversibly into fusion-competent trimers upon exposure to low pH, as found in the acidic environment of the endosome. The formation of trimers results in a conformational change in the hinge region of domain II, a key structural element that opens a ligand-binding hydrophobic pocket at the interface between domains I and II. The conformational change results in the exposure of a fusion peptide loop at the tip of domain II, which is required in the fusion step to drive the cellular and viral membranes together by inserting into the membrane .
YjbR-like superfamily (YjbR-like_sf)
Type: Homologous_superfamily

This entry represents the YjbR-like superfamily. Uncharacterised protein YjbR is predicted to contain the DNA binding domain comprising the 'double wing' motif .
EV matrix domain superfamily (EV_matrix_sf)
Type: Homologous_superfamily

Ebola virus sp. are non-segmented, negative-strand RNA viruses that causes severe haemorrhagic fever in humans with high rates of mortality. The virus matrix protein VP40 is a major structural protein that plays a central role in virus assembly and budding at the plasma membrane of infected cells. VP40 proteins associate with cellular membranes, interact with the cytoplasmic tails of glycoproteins, and bind to the ribonucleoprotein complex. The VP40 monomer consists of two domains, the N-terminal oligomerization domain and the C-terminal membrane-binding domain, connected by a flexible linker. Both the N-and C-terminal domains fold into β sandwich structures of similar topology . Within the N-terminal domain are two overlapping L-domains with the sequences PTAP and PPEY at residues 7 to13, which are required for efficient budding . L-domains are thought to mediate their function in budding through their interaction with specific host cellular proteins, such as tsg101 and vps-4 .

This entry represents the N- and C-terminal domains of the VP40 matrix protein.
PhnH-like superfamily (PhnH-like_sp)
Type: Homologous_superfamily

This entry represents the PhnH-like superfamily.

PhnH is an essential component of the C-P lyase core complex formed through the interaction with other Phn proteins (G, I and J). This core complex is involved in the C-P lyase pathway that converts phosphonate into 5-phosphoribosyl-alpha-1-diphosphate (PRPP) and is activated upon phosphate starvation in many bacterial species including Escherichia coli. In E. coli, the 14-cistron phn operon is required for phosphonate uptake and utilisation and encodes an ATP-binding cassette transporter (PhnC, PhnD, and PhnE), a regulatory protein (PhnF) and components required for enzymatic conversion of phosphonate into PRPP (PhnGHIJKLMNOP) .
KICSTOR complex protein C12orf66-like, central domain superfamily (C12orf66-like_central_sf)
Type: Homologous_superfamily

This entry represents the central domain of C12orf66-like proteins. Human C12orf66 is part of the KICSTOR complex that functions in the amino acid-sensing branch of the TORC1 signaling pathway .
ScdA-like, N-terminal domain superfamily (ScdA-like_N_sf)
Type: Homologous_superfamily

The Iron-sulfur cluster repair protein ScdA is involved in the repair of iron-sulfur clusters damaged by oxidative and nitrosative stress conditions . Structurally, ScdA is composed of five helices.

This superfamily represents the N-terminal domain of ScdA and related proteins.
L,D-transpeptidase catalytic domain-like (Transpep_catalytic_dom)
Type: Homologous_superfamily

The structure of L,D-transpeptidase from E. faecium is similar to that of Bacillus subtilis YkuD and consists of two domains. The C-terminal domain folds into a globular structure of the mainly beta class of protein structures . The residues of the proposed catalytic triad of YkuD (Cys139, His123, Asp124) are found in the C-terminal domain and correspond to residues Cys442, His421 and Asp422 of E. faecium L,D-transpeptidase. These proteins could catalyse similar reactions, but differences in the solvent accessibility of the catalytic Cys residues suggest that they may have different functions in peptidoglycan metabolism .
Influenza A virus NS1, effector domain-like superfamily (NS1A_effect_dom-like_sf)
Type: Homologous_superfamily

The influenza A virus NS1 protein contains an N-terminal RNA-binding domain and a C-terminal effector domain . This entry represents the C-terminal effector domain of the influenza A virus NS1 protein. The effector domain is able to interact with a variety of cellular and viral targets .
Tetrabrachion, parallel right-handed coiled coil domain (Tetrabrachion_parallel_CC)
Type: Homologous_superfamily

Tetrabrachion is a surface layer glycoprotein from the hyperthermophilic archaebacterium Staphylothermus marinus . The tetrabrachion protein complex consists of four identical subunits that form an α-helical coiled coil stalk anchored to the cell membrane that branches into four arms. Two molecules of the subtilisin-like protease STABLE are noncovalently bound near the centre of the stalk. This entry represents the protease binding region of the tetrabrachion complex, for which a right-handed coiled coil structure has been proposed. The parallel right-handed coiled-coil tetramer is stabilized by a complex pattern of complementary hydrophobic interactions between neighbouring helices .
Spc24, Fungi, globular domain superfamily (Spc24_Fungi_globular_sf)
Type: Homologous_superfamily

Spc24 is a component of the evolutionarily conserved kinetochore-associated Ndc80 complex, which is implicated in several essential outer kinetochore functions, including microtubule binding and control the spindle assembly checkpoint .

The Ndc80 complex appears to be a long rod with globular 'heads'. Ndc80 and Nuf2 contribute to one head and to the intervening shaft; Spc24 and Spc25 complete the shaft and contribute to the other head. Spc24 and Spc25 fold tightly together. The C-terminal globular domains of Spc24 and Spc25 form the 'inner' head, which faces the centromere .
YcgL-like superfamily (YcgL-like_sf)
Type: Homologous_superfamily

YcgL represents a conserved class of small proteins widespread in gammaproteobacteria. The YcgL domain contains two α-helices and four β-strands in the sequential arrangement β1-β2-α1-β3-α2-β4 as a 3-layer (α/β/α) sandwich .
Pelota/DOM34, N-terminal domain (Pelota/DOM34_N)
Type: Homologous_superfamily

Pelota (known as DOM34 in yeast) binds Hbs1, which is EF1-alpha-related subfamily GTPase, and is considered to play a crucial role in mRNA surveillance for protein synthesis . It is involved in No-go decay (NGD) and non-stop decay (NSD) surveillance mechanisms that target mRNAs on which elongation complexes are stalled. Pelota/Hbs1 were shown to promote dissociation of stalled elongation complexes and release of intact peptidyl-tRNA in the presence of the ATP-binding cassette protein ABCE1 . Pelota is conserved in eukaryotes and archaea .

Dom34 and Pelota are organised in three domains. The N-terminal domain, annotated as domain A in Pelota , represented by this entry, adopts a Sm-fold that is often involved in the recognition of mRNA stem loops or in the recruitment of mRNA degradation machinery .
Rv2632c-like superfamily (Rv2632c-like_sf)
Type: Homologous_superfamily

This entry includes a set of Actinobacterial proteins, including Rv2632c from Mycobacterium tuberculosis that is strongly implicated in the onset of non-replicating persistence, and thereby latent tuberculosis. Rv2632c contains a dsRBD-like (2 layers α/β) fold (PDBe:2fgg). It shares remarkable similarity with bacterial hibernation factors, despite very low sequence similarity. Based on this structure it was predicted that Rv1738, highly up-regulated in conditions that mimic the onset of persistence, helps trigger dormancy by association with the bacterial ribosome .
UROD/MetE-like superfamily (UROD/MetE-like_sf)
Type: Homologous_superfamily

Uroporphyrinogen decarboxylase (URO-D), the fifth enzyme of the haem biosynthetic pathway, catalyses the sequential decarboxylation of the four acetyl side chains of uroporphyrinogen to yield coproporphyrinogen . URO-D deficiency is responsible for the human genetic diseases familial porphyria cutanea tarda (fPCT) and hepatoerythropoietic porphyria (HEP). The sequence of URO-D has been well conserved throughout evolution. The best conserved region is located in the N-terminal section; it contains a perfectly conserved hexapeptide. There are two arginine residues in this hexapeptide which could be involved in the binding, via salt bridges, to the carboxyl groups of the propionate side chains of the substrate.

Methionine synthases catalyse the the final step of methionine biosynthesis. Two apparently unrelated families of proteins catalyse this step: cobalamin-dependent methionine synthase, which catalyses the transfer of a methyl group from N5-methyltetrahydrofolate to L-homocysteine and requires cobalamin as a cofactor (MetH; 5-methyltetrahydrofolate:L-homocysteine S-methyltransferase;

) and cobalamin-independent methionine synthase, which catalyses the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine without using an intermediate methyl carrier (MetE; 5-methyltetrahydropteroyltri-L-glutamate:L-homocysteine S-methyltransferase;

). These enzymes display no detectable sequence homology between them, but both require zinc for activation and binding to L-homocysteine. Organisms that cannot obtain cobalamin (vitamin B12) encode only the cobalamin-independent enzyme. Escherichia coli and many other bacteria express both enzymes . Mammals utilise only cobalamin-dependent methionine synthase, while plants and yeasts utilise only the cobalamin-independent enzyme.

The crystal structure of human uroporphyrinogen decarboxylase (URO-D) shows it is comprised of a single domain containing a (β/α)8-barrel with a deep active site cleft formed by loops at the C-terminal ends of the barrel strands . The cobalamin-independent methionine synthase MetE consists of a duplication of a related domain. Each domain is a (β/α)8-barrel with extended β-α loops. The barrels are arranged face to face and the extended β-α loops form the interface .
GspK, central domain superfamily (GspK_central_sf)
Type: Homologous_superfamily

This entry represents the central domain of the General secretion pathway protein K (GspK). Its structure is composed of a tandem repeat of two SAM-like domains inserted into pilin fold, with the first domain containing one classic HhH motif.
YkuJ-like superfamily (YkuJ-like_sf)
Type: Homologous_superfamily

YkuJ is a mixed α/β fold protein consisting of an antiparallel β-sheet with C- and N-terminal helices packed against one side (PDBe: 2ffg) . The function of YkuJ is not clear.
YfmB domain superfamily (YfmB_sf)
Type: Homologous_superfamily

This entry represents the YfmB domain superfamily. Its structure is composed of five helices, with a buried N-terminal helix. It presents some topological similarity to the Nucleotidyltransferase substrate binding subunit/domain (

)
RalF, C-terminal domain superfamily (RalF_C_sf)
Type: Homologous_superfamily

The Legionella pneumophila protein RalF is a guanine nucleotide exchange factor (GEF) of ADP-ribosylation factors (Arfs), activating and recruiting host Arf1 to the Legionella-containing vacuole . RalF contains an N-terminal Sec7 domain and a C-terminal domain known as Sec7-capping domain (SCD). The Sec7 domain of RalF has the same overall folded structure seen in eukaryotic Sec7 domains. The eukaryotic Sec7 domain is a catalytic domain found in guanine nucleotide exchange factors (GEFs) that is sufficient to activate Arf by stimulating GDP/GTP exchange . Structural studies showed that the C-terminal domain of RalF associates with the Sec7 domain to block access to the Arf-binding site . This entry represents the C-terminal domain of RalF .
MgtE, N-terminal domain superfamily (MgtE_N_sf)
Type: Homologous_superfamily

The Mg2+ transporter MgtE is an homodimeric transporter consisting of two cytosolic domains, the N-terminal domain and the CBS domain, and a C-terminal transmembrane domain with five membrane-spanning helices per monomer .

This domain is found at the N terminus of eubacterial magnesium transporters of the MgtE family

. This domain is an intracellular domain that has an α-helical structure. The crystal structure of the MgtE transporter shows two of 5 magnesium ions are in the interface between the N domain and the CBS domains. In the absence of magnesium there is a large shift between the N and CBS domains.
Troponin domain superfamily (Troponin_sf)
Type: Homologous_superfamily

The troponin (Tn) complex regulates Ca
2+
induced muscle contraction. Tn contains three subunits, Ca
2+
binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT). This entry includes domains from troponin T and troponin I. Troponin I binds to actin and troponin T binds to tropomyosin . Structurally this domain forms a heterodimeric coiled coil.
PhoU-like domain superfamily (PhoU-like_sf)
Type: Homologous_superfamily

This entry represents the PhoU superfamily, it also includes Putative inorganic phosphate export protein YjbB and uncharacterised prokaryotic proteins.

PhoU proteins are known to play a role in the regulation of phosphate uptake. The PhoU domain is composed of a three helix bundle . The PhoU protein contains two copies of this domain. The domain binds to an iron cluster via its conserved E/DXXXD motif. Deletion of PhoU activates constitutive expression of the phosphate ABC transporter and allows phosphate transport, but causes a growth defect; suggesting that the protein has some secondary function . The crystal structure of PHOU_AQUAE reveals two similar coiled-coil PhoU domains, each forming a three-helix bundle .
PA2021-like domain superfamily (PA2021-like_sf)
Type: Homologous_superfamily

This domain superfamily of proteins with unknown function appears to be restricted to Gammaproteobacteria.
Kinase associated protein B superfamily (KapB_sf)
Type: Homologous_superfamily

Kinase associated protein B (KapB) is one of the major histidine kinases that provide phosphate input in the phosphorelay to produce SpoOA approximately P, the key transcription factor controlling the initiation of sporulation in Bacillus subtilis . It forms an anti-parallel β sheet with an extending α helical region.
CalX-like domain superfamily (CalX-like_sf)
Type: Homologous_superfamily

The calx-β motif is present as a tandem repeat in the cytoplasmic domains of Calx Na-Ca exchangers, which are used to expel calcium from cells. This motif overlaps domains used for calcium binding and regulation. The calx-β motif is also present in the cytoplasmic tail of mammalian integrin-beta4, which mediates the bi-directional transfer of signals across the plasma membrane, as well as in some cyanobacterial proteins. This motif is also found in Fras1/Frem family of extracellular proteins (extracellular matrix organizing protein FRAS1 and FRAS1-related extracellular matrix proteins FRAM1, 2 and 3) required for proper organogenesis during embryonic development and whose mutations lead to Fraser Syndrome, a rare congenital disorder characterised by multisystem malformation usually comprising abnormal brain formation, cryptophthalmos, syndactyly and renal defects . This motif contains a series of β-strands and turns that form a self-contained β-sheet .
YopT domain superfamily (YopT_sf)
Type: Homologous_superfamily

The function of the YopT protein is not known, though it has been structurally characterised. The protein is a homo-dimer, with each monomer consisting of one α helix and three β strands.
Non-structural protein NSP3A domain-like superfamily (NSP3A-like)
Type: Homologous_superfamily

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

The ubiquitin-like domain 1 (Ubl1) and the Glu-rich acidic region are located at the N-terminal of NSP3. These two regions together are also named "NSP3A". In addition to the four β-strands and two α-helices that are common to ubiquitin-like folds, the globular domain of NSP3A contains two short helices . NSP3A is well conserved within different SARS-CoV sequences but exhibits low sequence identity (less than 35%) to other CoV NSP3 proteins . It is an essential component of the replication/transcription complex and is involved in multiple biological processes, such as proteolysis and RNA processing .

This entry represents NSP3A that has been shown to bind ssRNA. The overall structure of the SARS-CoV Ubl1 domain is similar to human ubiquitin (Ub) and that of each of the two ubiquitin-like domains of human or mouse interferon-stimulated gene 15 (hISG15 or mISG15). It is also similar to the Ras-interacting domain (RID) of RalGDS .
Corrinoid adenosyltransferase PduO/GlcC-like superfamily (PduO/GlcC-like_sf)
Type: Homologous_superfamily

This entry includes Protein GlcG from Escherichia coli, Corrinoid adenosyltransferase PduO from Salmonella typhimurium and many uncharacterised proteins from bacteria and fungi. GlcG controls the expression of the genes of the glycolate pathway . The structure of GlcG is composed of an α-β(2)-α(3)-β(2)-α fold, similar to the Roadblock/LC7 domain. PduO converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), the cofactor for propanediol dehydratase .

Extracellular haem-binding protein from Streptomyces reticuli (HbpS,

) is also included in this entry. This protein interacts with the SenS/SenR two-component signal transduction system. Iron binds to surface-exposed lysine residues of an octomeric assembly of the protein .

This entry also includes the formaldehyde-sensing protein EfgA that directly binds formaldehyde and causes rapid growth arrest and cessation of translation in response to elevated levels of formaldehyde .
RNase P subunit Pop5/Rpp14/Rnp2-like domain superfamily (Rnp2-like_sf)
Type: Homologous_superfamily

This superfamily contains ribonuclease P (Rnp) proteins from eukaryotes and archaea. Rnp is a ubiquitous ribozyme that catalyzes a Mg2+-dependent hydrolysis to remove the 5'-leader sequence of precursor tRNA (pre-tRNA) . Archaeal and eukaryote RNase P consist of a single RNA and archaeal RNase P has four or five proteins, while eukaryotic RNase P consists of 9 or 10 proteins. Eukaryotic and archaeal RNase P RNAs cooperatively function with protein subunits in catalysis .

Eukaryotic nuclear RNase P shares most of its protein components with another essential RNP enzyme, nucleolar RNase MRP . RNase MRP (mitochondrial RNA processing) is an rRNA processing enzyme that cleaves a specific site within precursor rRNA to generate the mature 5'-end of 5.8S rRNA . Despite its name, the vast majority of RNase MRP is localized in the nucleolus . RNase MRP has been shown to cleave primers for mitochondrial DNA replication and CLB2 mRNA. In yeast, RNase MRP possesses one putatively catalytic RNA and at least 9 protein subunits (Pop1, Pop3-Pop8, Rpp1, Snm1 and Rmp1) .

Human RNase P is composed of a singular protein Pop1 and three subcomplexes, the Rpp20-Rpp25 heterodimer, Pop5-Rpp14-(Rpp30)2-Rpp40 heteropentamer, and Rpp21-Rpp29-Rpp38 heterotrimer .

In the hyperthermophilic archaeon Pyrococcus horikoshii OT3, RNase P is composed of the RNase P RNA (pRNA) and five proteins (PhoPop5, PhoRpp38, PhoRpp21, PhoRpp29, and PhoRpp30) .

Proteins in this entry include Rnp2 (also known as Pop5) from archaea and Pop5/Rpp14 from humans. In eukaryotes Pop5 is a subunit of both the Rnp and MRP complexes. Although both Pop5 and Rpp14 have similar protein structure, they share a very limited sequence similarity. Moreover, the C-terminal fragments after the conserved β sheets in Pop5 and Rpp14 exhibit distinct structural features that mediate interactions with Pop1 and Rpp40, respectively .

The structure of Rnp2 (ribonuclease P protein component 2) has a ferrodoxin-like fold composed of an α-β sandwich with antiparallel β-sheet and contains an extra C-terminal helix.
DUF2789 superfamily (DUF2789_sf)
Type: Homologous_superfamily

This bacterial superfamily of proteins has no known function.
DNA-directed RNA polymerase subunit delta, N-terminal domain superfamily (RNAP_delta_N_dom_sf)
Type: Homologous_superfamily

This entry includes DNA-directed RNA polymerase subunit delta from Bacillus subtilis.

The delta protein is a dispensable subunit of Bacillus subtilis RNA polymerase (RNAP) that has major effects on the biochemical properties of the purified enzyme. In the presence of delta, RNAP displays an increased specificity of transcription, a decreased affinity for nucleic acids, and an increased efficiency of RNA synthesis because of enhanced recycling . The delta protein, contains two distinct regions, an ordered N-terminal domain and a glutamate and aspartate residue-rich C-terminal region, unordered and flexible . It participates in both the initiation and recycling phases of transcription and also in the adaptation to changes in the environment.

This superfamily represents the N-terminal domain of the delta subunit that adopts a DNA/RNA-binding three-helical bundle fold and was shown to interact with RNAP .
DELLA, N-terminal domain superfamily (DELLA_N_sf)
Type: Homologous_superfamily

Gibberellins are plant hormones which have great impact on growth signalling. DELLA proteins are transcriptional regulators of growth related proteins that lack a DNA binding domain and exert its negative regulation of gibberellin responses through interaction with other transcription factors . DELLAs are downregulated when gibberellins bind to their receptor GID1 , which forms a complex with DELLA proteins and signals them towards 26S proteasome. The N-terminal of DELLA proteins contains conserved DELLA and TVHYNP motifs which are important for GID1 binding and proteolysis of the DELLA proteins .