SII-SWORD/CoKE huggingface dataset:
Nucleocapsid protein, N-terminal (Nucleocapsid_N)
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 N-terminal domain of the nucleocapsid (N) protein predominantly from Coronavirus. It exhibits a U-shaped structure, with two arms rich in basic residues, providing a module for specific interaction with RNA . The overall structure of the N-terminal domain found in SARS-CoV-2 is similar to other reported coronavirus nucleocapsid protein N-terminal domains, but the surface charge distribution patterns are different. This domain also interacts with the viral membrane protein during virion assembly and plays a critical role in enhancing the efficiency of virus transcription and assembly. It has been identified as an important drug target .
HSP90, C-terminal domain (HSP90_C)
Type: Homologous_superfamily

Molecular chaperones, or heat shock proteins (Hsps) are ubiquitous proteins that act to maintain proper protein folding within the cell . They assist in the folding of nascent polypeptide chains, and are also involved in the refolding of denatured proteins following proteotoxic stress. As their name implies, the heat shock proteins were first identified as proteins that were up-regulated under conditions of elevated temperature. However, subsequent studies have shown that increased Hsp expression is induced by a variety of cellular stresses, including oxidative stress and inflammation. Five major Hsp families have been determined, and are categorized according to their molecular size (Hsp100, Hsp90, Hsp70, Hsp60, and the small Hsps). Hsps are involved in a variety of cellular processes that are ATP-dependent. These include: prevention of protein aggregation, protein degradation, protein trafficking, and maintenance of signalling proteins in a conformation that permits activation.

Hsp90 chaperones are unique in their ability to regulate a specific subset of cellular signalling proteins that have been implicated in disease processes, including intracellular protein kinases, steroid hormone receptors, and growth factor receptors .

This entry represents the C-terminal domain of HPS90. Structurally, this domain has an α-β(3)-α(3) fold arranged in two layers (α/β) with mixed β-sheet and crossing loops.
WWE domain superfamily (WWE_dom_sf)
Type: Homologous_superfamily

The WWE domain is named after three of its conserved residues and is predicted to mediate specific protein-protein interactions in ubiquitin and ADP ribose conjugation systems. This domain is found as a tandem repeat at the N-terminal of Deltex, a cytosolic effector of Notch signalling thought to bind the N-terminal of the Notch receptor . It is also found as an interaction module in protein ubiquination and ADP ribosylation proteins .

Structurally, the WWE domain has a β(2)-α-β(4) fold with antiparallel folded β-sheet (half-barrel).
MutL, C-terminal domain superfamily (MutL_C_sf)
Type: Homologous_superfamily

MutL and MutS are key components of the DNA repair machinery that corrects replication errors . MutS recognises mispaired or unpaired bases in a DNA duplex and in the presence of ATP, recruits MutL to form a DNA signalling complex for repair. The N-terminal region of MutL contains the ATPase domain and the C-terminal is involved in dimerisation .

The structure of the C-terminal domain of MutL consists of two different α+β (sub)domains, both composed of two layers (α/β) with antiparallel sheet, where the second domain is inserted in the first one.
Phosphoprotein, C-terminal (PP_M1_C)
Type: Homologous_superfamily

This superfamily includes the C-terminal domain of the M1 phosphoprotein non-structural RNA polymerase alpha subunit (

) from various strains of Rabies virus . The M1 phosphoprotein is thought to be a component of the active polymerase, and may be involved in template binding. Structurally, this domain consists of six helices and one β-hairpin.
Pre-mRNA-splicing factor Isy1 superfamily (Isy1_sf)
Type: Homologous_superfamily

This entry includes yeast Isy1 and it's homologues from plants and animals. In budding yeast, Isy1 is part of the NineTeen Complex (NTC), which is involved in spliceosome activation by specifying the interaction of U5 and U6 with pre-mRNA for their stable association with the spliceosome after U4 dissociation . The S. pombe homologue is known as Cwf12.
Calcyclin-binding protein, N-terminal (CacyBP_N)
Type: Homologous_superfamily

The N-terminal domain of Calcyclin-binding protein (CacyBP) adopts a helical hairpin structure with a hydrophobic core stabilised by a classic knobs-and-holes arrangement of side chains contributed by the two amphipathic helices. Little is known about this domain's function, except that it is crucial for interactions with Siah. It has also been hypothesised that CacyBP can dimerise through this N-terminal domain .
ESCRT assembly domain (ESCRT_assembly_dom)
Type: Homologous_superfamily

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .
Type III secretion, needle-protein-like superfamily (T3SS_needle-like_sf)
Type: Homologous_superfamily

This entry represents bacterial type III secretion system needle-like proteins. Type III secretion systems are essential virulence determinants for many Gram-negative bacterial pathogens, acting to translocate proteins, usually virulence factors, out across both inner and outer membranes of bacteria and into the cytoplasm of the host cell .
Non-structural protein NSP7 superfamily, coronavirus (NSP7_sf_CoV)
Type: Homologous_superfamily

Non-structural protein NSP7 has been implicated in viral RNA replication and is predominantly α-helical in structure. Its central core is an N-terminal helical bundle (HB), with helices HB1, HB2 and HB3, forming a triple-stranded antiparallel coiled coil with a right-handed superhelical pitch. It is part of the RNA-dependent RNA polymerase (RdRp) heterotetramer which consists of one NSP7, two NSP8 molecules and the catalytic NSP12, defined as the minimal core component for mediating coronavirus RNA synthesis . NSP7 and NSP8 forms a complex that adopts a hollow cylinder-like structure . The dimensions of the central channel and positive electrostatic properties of the cylinder imply that it confers processivity on RNA-dependent RNA polymerase . NSP7 and NSP8 play a role in the stabilisation of NSP12 regions involved in RNA binding, and are essential for a highly active NSP12 polymerase complex .
ChaB superfamily (ChaB_sf)
Type: Homologous_superfamily

This superfamily of proteins contain a conserved 60 residue region. This protein is known as ChaB in Escherichia coli and is found next to ChaA, which is a cation transporter protein . ChaB may regulate ChaA function in some way.

Structurally, ChaB consists of three helices, where the first one is shorter than the other two. It has a bundle fold, capped by a small C-terminal β-hairpin.
VPS28, C-terminal domain superfamily (VPS28_C_sf)
Type: Homologous_superfamily

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .

This superfamily represents the C-terminal domain of VPS28.
NADH-ubiquinone oxidoreductase 51kDa subunit, iron-sulphur binding domain superfamily (Nuop51_4Fe4S-bd_sf)
Type: Homologous_superfamily

This superfamily represents the iron-sulphur binding domain of NADH-ubiquinone oxidoreductase 51kDa subunit from NADH:ubiquinone oxidoreductase.

Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 51kDa (in mammals), which is the second largest subunit of complex I . The 51kDa subunit, as the corresponding bacterial subunit (Nqo1 in Thermus and NuoF in E. coli) , contains the NADH-binding site, the primary electron acceptor FMN-binding site, and a 4Fe-4S cluster .
Aspartyl-phosphate phosphatase Spo0E-like superfamily (Spo0E-like_sf)
Type: Homologous_superfamily

Spo0E is an aspartyl-phosphate phosphatase which specifically dephosphorylates the sporulation transcription factor Spo0A-P and negatively regulates the sporulation initiation pathway in order to control the proper timing of sporulation . The structure of Spo0E has revealed an anti-parallel α-helical structure .

Spore formation is an extreme response to starvation and can also be a component of disease transmission. Sporulation is controlled by an expanded two-component system where starvation signals result in sensor kinase activation and phosphorylation of the master sporulation response regulator Spo0A. Phosphatases such as Spo0E dephosphorylate Spo0A thereby inhibiting sporulation .
RNA-binding protein B2 superfamily (RNA-bd_B2_sf)
Type: Homologous_superfamily

Protein B2 binds double-strand RNA (dsRNA) with high affinity and suppresses the host RNA silencing-based antiviral response. B2 is expressed by the insect Flock House virus (FHV) as a counter-defense mechanism against antiviral RNA silencing during infection. In vitro, B2 binds to dsRNA as a dimer and inhibits the cleavage of it by Dicer. B2 blocks cleavage of the FHV genome by Dicer and also the incorporation of FHV small interfering RNAs into the RNA-induced silencing complex .
YoaC-like superfamily (YoaC-like_sf)
Type: Homologous_superfamily

This superfamily consist of the hypothetical bacterial protein YoaC. Its structure is composed of five helices arranged in bundle, it has one crossover connection and the arrangement of the first four helices is similar to the KaiA/RbsU domain fold (

).
Bacteriophage DNA replication protein Gp16.7 superfamily (Phage_DNA_replic_GP16.7_sf)
Type: Homologous_superfamily

The early-expressed gene 16.7 is conserved in bacteriophage phi-29 and related phages. It encodes a membrane protein, GP16.7, consisting of an N-terminal transmembrane domain and a C-terminal DNA-binding and dimerisation domain. GP16.7 plays an important role in organising membrane-associated bacteriophage DNA replication . The C-terminal domain has a similar secondary structure similar to homeodomains, but forms a fundamentally different tertiary structure consisting of a six-helical dimeric fold . Multimerisation of this dimer leads to efficient DNA binding.
Mediator complex, subunit Med7/Med21-like (Med7/Med21-like)
Type: Homologous_superfamily

The Mediator complex is a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. The Mediator complex, having a compact conformation in its free form, is recruited to promoters by direct interactions with regulatory proteins and serves for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. On recruitment the Mediator complex unfolds to an extended conformation and partially surrounds RNA polymerase II, specifically interacting with the unphosphorylated form of the C-terminal domain (CTD) of RNA polymerase II. The Mediator complex dissociates from the RNA polymerase II holoenzyme and stays at the promoter when transcriptional elongation begins.

The Mediator complex is composed of at least 31 subunits: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11.

This superfamily represents the MED7 and MED21 subunits.
MED7 works as a co-activator with the factors responsible of the activation of gene transcription in metazoans, it directs the transcriptional initiation by the RNA polymerase II apparatus .
MED21 has been known as Srb7 in yeasts, hSrb7 in humans and Trap 19 in Drosophila.
The heterodimer of the two subunits MED7 and MED21 appears to act as a hinge between the middle and the tail regions of Mediator .
RUN domain superfamily (Run_dom_sf)
Type: Homologous_superfamily

The RUN domain, named after RPIP8, unc-14 and NESCA, is organised into six conserved blocks (A-F), which constitute the 'core' of a globular structure tolerating insertions of considerable length between the conserved blocks . The RUN domain is found in one or two copies in several proteins that are linked particularly to the functions of GTPases in the Rap and Rab families. This domain is thought to be a specific effector of small GTPases, but in the case of many of RUN domains their specific partners and their roles need to be determined. RUN domains can be associated with TBC/rab GAP, FYVE, DENN, SH3, DAG/PE-binding, PLAT/LH2, PH or PX domains. The RUN domain may have a role in the interaction of various proteins with cytoskeletal filaments .

Structurally, the RUN domain comprises eight anti-parallel α-helices, which form an extensive hydrophobic core, followed by an extended segment .
TROVE domain superfamily (TROVE_dom_sf)
Type: Homologous_superfamily

The TROVE (Telomerase, Ro and Vault) domain is a module of ~300-500 residues that is found in TEP1 and Ro60 the protein components of three ribonucleoprotein particles. It is also found in bacterial ribonucleoproteins suggesting an ancient origin of these ribonucleoproteins. It can be found associated with other domains, such as the VWFA domain, the TEP1 N-terminal domain, the NACHT-NTPase domain, and WD-40 repeats. This domain may be involved in binding the RNA components of the three RNPs, which are telomerase RNA, Y RNA and vault RNA .

The TROVE domain contains a few absolutely conserved residues. As none of these conserved residues are the polar type of amino acids found in active sites, it seems unlikely that this region has an enzymatic function .

Structurally, the TROVE domain consist of two superhelical sections arranged like a horse-shoe.
GUN4-like superfamily (GUN4-like_sf)
Type: Homologous_superfamily

GUN4 is a porphyrin-binding protein involved in chlorophyll biosynthesis regulation and intracellular signaling, found in aerobic photosynthetic organisms . It has been implicated in retrograde signalling between the chloroplast and nucleus . GUN4 can bind protoporphyrin IX (PIX) and magnesium protoporphyrin IX (MgPIX), substrate and product of the Mg-chelatase, as well as heme and cobalt protoporphyrin IX (CoPIX) . It may play a role in protecting plants from reactive oxygen species (ROS)-mediated damage .

GUN4 has a multihelical structure composed of an open array, trapping inside an extended region before the C-terminal helix.
DNA terminal protein Gp3 superfamily (DNA_terminal_Gp3_sf)
Type: Homologous_superfamily

The DNA terminal protein Gp3, found in a number of Bacillus phages, is linked to the 5' ends of both strands of the genome through a phosphodiester bond between the β-hydroxyl group of a serine residue and the 5'-phosphate of the terminal deoxyadenylate. This protein is essential for DNA replication and is involved in the priming of DNA elongation .

Gp3 has a multihelical structure arranged as an open array. It contains a C-terminal four-helical bundle with a left-handed superhelix.
Tryptophan/Indoleamine 2,3-dioxygenase-like (Trp/Indoleamine_2_3_dOase-like)
Type: Homologous_superfamily

This superfamily represents the tryptophan and indoleamine 2,3-dioxygenase.

Tryptophan 2,3-dioxygenase (

) enzymes are involved in tryptophan metabolism, which catalyses the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring .

Indoleamine 2,3-dioxgyenase (IDO,

) is a cytosolic heme protein which, together with the hepatic enzyme tryptophan 2,3-dioxygenase, catalyses the conversion of tryptophan and other indole derivatives to kynurenines. It is widely distributed in human tissues, involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses . The degradative action of IDO on tryptophan leads to cell death by starvation of this essential and relatively scarce amino acid. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. IDO also acts as a suppressor of anti-tumor immunity and limits the growth of intracellular pathogens by depriving tryptophan. Elevated IDO1 expression is a hallmark of major viral infections including HIV, HBV, HCV or influenza and also of major bacteria infections . This enzyme has also been associated to protection of the fetus from maternal immune rejection . Indoleamine 2,3-dioxygenase from yeast (BNA2) plays a role in the cellular response to telomere uncapping . IDO is a heme-containing enzyme of about 400 amino acids. Site-directed mutagenesis showed His346 (

) to be essential for haem binding, indicating that this histidine residue may be the proximal ligand. Mutation of Asp274 also compromised the ability of IDO to bind haem, suggesting that Asp274 may coordinate to heme directly as the distal ligand or is essential in maintaining the conformation of the haem pocket .

There are two IDO enzyme catalysing the same reaction, IDO1 and IDO2 which differ in their affinity for tryptophan being IDO2 affinity for tryptophan much lower than that of IDO1. 50% of Caucasians harbor polymorphisms which abolish IDO2 enzymatic activity. IDO2 is expressed in human tumors in an inactive form, thus, tryptophan degradation is entirely provided by IDO1 in these cells . IDO2 may play a role as a negative regulator of IDO1 by competing for heme-binding with IDO1. ALthough low efficiency IDO2 enzymes have been conserved throughout vertebrate evolution, higher efficiency IDO1 enzymes are dispensable in many lower vertebrate lineages . It is suggested that IDO1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.

Other proteins that are evolutionarily related to IDO include myoglobin from the red muscle of the archaeogastropodic molluscs, Nordotis madaka (Giant abalone) and Sulculus diversicolor . These unusual globins lack enzymatic activity but have kept the heme group.
PTPA superfamily (PTPA_sf)
Type: Homologous_superfamily

Phosphotyrosyl phosphatase activator (PTPA, also known as protein phosphatase 2A activator) proteins stimulate the phosphotyrosyl phosphatase (PTPase) activity of the dimeric form of protein phosphatase 2A (PP2A). PTPase activity in PP2A (in vitro) is relatively low when compared to the better recognised phosphoserine/ threonine protein phosphorylase activity. It also reactivates the serine/threonine phosphatase activity of an inactive form of PP2A. The specific biological role of PTPA is unknown. PTPA has been suggested to play a role in the insertion of metals to the PP2A catalytic subunit (PP2Ac) active site, to act as a chaperone, and more recently, to have peptidyl prolyl cis/trans isomerase activity that specifically targets human PP2Ac . Together, PTPA and PP2A constitute an ATPase and it has been suggested that PTPA alters the relative specificity of PP2A from phosphoserine/phosphothreonine substrates to phosphotyrosine substrates in an ATP-hydrolysis-dependent manner. Basal expression of PTPA depends on the activity of a ubiquitous transcription factor, Yin Yang 1 (YY1). The tumour suppressor protein p53 can inhibit PTPA expression through an unknown mechanism that negatively controls YY1 .

PTPA as a multihelical structure fold.
Peptidase M41-like (Peptidase_M41-like)
Type: Homologous_superfamily

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

This group of metallopeptidases belong to MEROPS peptidase family M41 (FtsH endopeptidase family, clan MA(E)). The predicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH.

The peptidase M41 family belong to a larger family of zinc metalloproteases. This family includes the cell division protein FtsH, and the yeast mitochondrial respiratory chain complexes assembly protein, which is a putative ATP-dependent protease required for assembly of the mitochondrial respiratory chain and ATPase complexes. FtsH is an integral membrane protein, which seems to act as an ATP-dependent zinc metallopeptidase that binds one zinc ion.
H-type lectin domain superfamily (H-type_lectin_dom_sf)
Type: Homologous_superfamily

The H-type lectin domain is a unit of six beta chains, combined into a homo-hexamer. It is involved in self/non-self recognition of cells, through binding with carbohydrates. The name (H-type) is derived from Helix pomatia agglutinin (HPA), a N-acetylgalactosamine (GalNAc) binding lectin .