SII-SWORD/CoKE huggingface dataset:
Hemagglutinin-esterase (HEMA)
Type: Family

Haemagglutinin-esterase fusion glycoprotein (HEF) is a multi-functional protein embedded in the viral envelope of several viruses, including influenza C virus, coronaviruses (in particular, Betacoronavirus members of subgenus Embecovirus, previously known as group 2a coronaviruses) and toroviruses . HEF is required for infectivity, and functions to recognise the host cell surface receptor, to fuse the viral and host cell membranes, and to destroy the receptor upon host cell infection. The haemagglutinin region of HEF is responsible for receptor recognition and membrane fusion, and bears a strong resemblance to the sialic acid-binding haemagglutinin found in influenza A and B viruses, except that it binds 9-O-acetylsialic acid. The esterase region of HEF is responsible for the destruction of the receptor, an action that is carried out by neuraminidase in influenza A and B viruses. The esterase domain is similar in structure to Streptomyces scabies esterase, and to acetylhydrolase, thioesterase I and rhamnogalacturonan acetylesterase.

The haemagglutinin-esterase glycoprotein HEF must be cleaved by the host's trypsin-like proteases to produce two peptides (HEF1 and HEF2) in order for the virus to be infectious. Once HEF is cleaved, the newly exposed N-terminal of the HEF2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the virus to infect the host cell.

The haemagglutinin-esterase glycoprotein is a trimer, where each monomer is composed of three domains: an elongated stem active in membrane fusion, an esterase domain, and a receptor-binding domain, where the stem and receptor-binding domains together resemble influenza A virus haemagglutinin. Two of these domains are composed of non-contiguous sequence: the receptor-binding haemagglutinin domain is inserted into a surface loop of the esterase domain, and the esterase domain is inserted into a surface loop of the haemagglutinin stem.
Outer capsid protein VP4 (Rota_A_VP4)
Type: Family

The spike protein VP4 is a key component of the membrane penetration apparatus of rotavirus .
Nucleocapsid protein, gammacoronavirus (NCAP_gCoV)
Type: Family

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.

Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins .

It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection .

This entry represents the nucleocapsid protein from gammacoronavirus.
Nucleocapsid protein, alphacoronavirus (NCAP_aCoV)
Type: Family

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.

Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins .

It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection .

This entry represents the nucleocapsid protein from alphacoronavirus.
M matrix/glycoprotein, gammacoronavirus (GAMMA_CORONA_M)
Type: Family

This family consists of various Gammacoronavirus matrix proteins which are transmembrane glycoproteins.

M proteins play a critical role in protein-protein interactions (as well as protein-RNA interactions) since virus-like particle (VLP) formation in many coronavirus requires only the M and envelope (E) proteins for efficient virion assembly . The M protein or E1 glycoprotein is implicated in virus assembly . The E1 viral membrane protein is required for formation of the viral envelope and is transported via the Golgi complex .
M matrix/glycoprotein, alphacoronavirus (ALPHA_CORONA_M)
Type: Family

This family consists of various Alphacoronavirus matrix proteins which are transmembrane glycoproteins.

M proteins play a critical role in protein-protein interactions (as well as protein-RNA interactions) since virus-like particle (VLP) formation in many coronavirus requires only the M and envelope (E) proteins for efficient virion assembly . The M protein or E1 glycoprotein is implicated in virus assembly . The E1 viral membrane protein is required for formation of the viral envelope and is transported via the Golgi complex .
Spike glycoprotein, Alphacoronavirus (ALPHA_CORONA_SPIKE)
Type: Family

Coronovirus enter target cells through fusion of viral and cellular membranes mediated by the viral envelope glycoprotein S. Trimers of Coronovirus S glycoprotein constitute the typical viral spikes. The precursor S protein is processed by host cell furin or furin-like protease to yield the mature S1 and S2 proteins .

This entry represents the spike glycoprotein from Alphacoronavirus.
TSC22 domain family protein 4 (TSC22D4)
Type: Family

TSC22 domain family protein 4 (TSC22D4) is a transcription factor that regulates hepatic lipid metabolism during cancer cachexia and acts as a checkpoint in systemic glucose metabolism in both mice and human
.
StAR-related lipid transfer protein 4 (StarD4)
Type: Family

StAR-related lipid transfer protein 4 (StarD4) contains a steroidogenic acute regulatory-related lipid transfer (START) domain, a lipid binding domain which appears in a wide range of proteins involved in several cellular functions . StarD4 is an intracellular cholesterol transporter that plays an important role in the maintenance of cellular cholesterol homeostasis. It binds free cholesterol and increases cholesteryl ester formation . It is also involved in translocation of 7-hydroperoxycholesterol to isolated mitochondria . The expression of StarD4 can be sterol-repressed through the SREBP-2 pathway .
Ubiquitin-protein ligase E3A, N-terminal zinc-binding domain superfamily (AZUL_sf)
Type: Homologous_superfamily

The AZUL or amino-terminal zinc-binding domain of ubiquitin E3a ligase (Ube3A) is found in eukaryotes, and is an unusual zinc-finger domain. The final cysteine is usually mutated in Angelman syndrome patients. It is likely that AZUL plays a role in Ube3A substrate-recognition .

The AZUL domain has a helix-loop-helix architecture with a Zn ion coordinated by four Cys residues arranged in Cys-X(4)-Cys-X(4)-Cys-X(28)-Cys motif .
SCO4226, nickel-binding ferredoxin-like monomer (SCO4226)
Type: Homologous_superfamily

This superfamily entry represents the open reading frame SCO4226 of Streptomyces coelicolor A3(2), which encodes an 82-residue hypothetical protein. Most of these proteins are found in bacteria and archaea, though are functionally uncharacterised. Biochemical assays revealed that each SCO4226 dimer binds four nickel ions. Each subunit of SCO4226 dimer adopts a canonical ferredoxin-like fold with five β-strands flanked by two α-helices. In the structure of Ni-SCO4226, four nickel ions are coordinated at the surface of the dimer. Further biochemical assays suggested that the binding of Ni2 triggers the self-aggregation of SCO4226 in vitro. All these results suggested that SCO4226 acts as a nickel binding protein, probably required for nickel sequestration and/or detoxification. Additionally, there is a single completely conserved residue C that may be functionally important .
Glutaminyl-tRNA synthetase, class Ib, non-specific RNA-binding domain, N-terminal, subdomain 1 (Gln-tRNA-synth_Ib_RNA-bd_N_1)
Type: Homologous_superfamily

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The N-terminal appended domain (NTD) of glutaminyl-tRNA synthetase consists consists of two α helical domains, the first from containing a seven-helix bundle, and the second containing a four-helix bundle, which are connected by a seven residue linker . It is thought to bind RNA in a non-specific manner, enhancing interactions between the tRNA and enzyme, but is not essential for enzyme function .

This superfamily represents the subdomain 1 found at the N-terminal of glutaminyl-tRNA synthetase (

) in eukaryotes but not in Escherichia coli.
Glutaminyl-tRNA synthetase, class Ib, non-specific RNA-binding domain, N-terminal, subdomain 2 (Gln-tRNA-synth_Ib_RNA-bd_N_2)
Type: Homologous_superfamily

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The N-terminal appended domain (NTD) of glutaminyl-tRNA synthetase consists consists of two α helical domains, the first from containing a seven-helix bundle, and the second containing a four-helix bundle, which are connected by a seven residue linker . It is thought to bind RNA in a non-specific manner, enhancing interactions between the tRNA and enzyme, but is not essential for enzyme function .

This superfamily represents the subdomain 2 found at the N-terminal of glutaminyl-tRNA synthetase (

) in eukaryotes but not in Escherichia coli.
Exocyst component Exo84, C-terminal, subdomain 2 (Exo84_C_2)
Type: Homologous_superfamily

The exocyst is a large complex that is required for tethering vesicles at the final stages of the exocytic pathway in all eukaryotes. Exocyst subunits are composed of mostly helical modules strung together into long rods .

This superfamily represents the subdomain 2 found in the C-terminal helical region of the exocyst component Exo84. The C-terminal region resembles a cullin-repeat, a multi-helical bundle.
Exocyst component Exo84, C-terminal, subdomain 1 (Exo84_C_1)
Type: Homologous_superfamily

The exocyst is a large complex that is required for tethering vesicles at the final stages of the exocytic pathway in all eukaryotes. Exocyst subunits are composed of mostly helical modules strung together into long rods .

This superfamily represents the subdomain 1 found in the C-terminal helical region of the exocyst component Exo84. The C-terminal region resembles a cullin-repeat, a multi-helical bundle.
Small ribosomal subunit protein eS8 subdomain, eukaryotes (Ribosomal_protein_eS8_euk)
Type: Homologous_superfamily

This superfamily represents a subdomain of the ribosomal protein eS8 from eukaryotes. This domain consists of 3 helices.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
CRISPR-associated endoribonuclease Cas6/Csy4, subtype I-F/YPEST superfamily (CRISPR-Cas6/Csy4_sf)
Type: Homologous_superfamily

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.

This protein family, typified by YPO2462 of Yersinia pestis, is a CRISPR-associated (Cas) family strictly associated with the Ypest subtype of CRISPR/Cas locus. It is designated Csy4, for CRISPR/Cas Subtype Ypest protein 4. In Pseudomonas aeruginosa, crRNA biogenesis requires the endoribonuclease Csy4, which binds and cleaves the repetitive sequence of the CRISPR transcript .

The crystal structure of Csy4 in complex with its cognate RNA reveals an unexpected recognition mechanism whereby Csy4 makes sequence-specific interactions in the major groove of the CRISPR repeat stem-loop. Together with electrostatic contacts to the phosphate backbone, these enable Csy4 to selectively bind and cleave pre-crRNAs .
Type VII secretion system EssB, C-terminal (T7SS_EssB_C)
Type: Homologous_superfamily

This superfamily includes proteins homologous to YukC in B. subtilis and EssB in Staphylococcus aureus. The YukC protein family is thought to participate to the formation of a translocon required for the secretion (type VII secretion) of WXG100 proteins (

) in monoderm bacteria, the WXG100 protein secretion system (Wss) (

). The membrane-bound EssB is an integral and essential component of the bacterial type VII secretion system that can contribute to pathogenicity. The asymmetric unit consists of a single polypeptide folded into an elongated structure, which consists of two domains. This superfamily represents the C-terminal segment, which is positioned on the exterior of the membrane and adopts a helical fold. This segment contributes most to dimer formation. The domain may serve as an anchor point for the secretion apparatus, which is embedded in the cytoplasmic membrane, the C-terminal domain protruding out to interact with partner proteins or components of peptidoglycan .
L1 transposable element, C-terminal domain (L1_C)
Type: Homologous_superfamily

This superfamily represents a conserved component in the protein ORF1 of the long interspersed nuclear element 1 (LINE-1 or L1) retrotransposon. This domain is designated C-terminal and its sole function is to assist RNA binding to the central RRM domain .
Spindlin/spermiogenesis-specific domain superfamily (SPIN/Ssty_sf)
Type: Homologous_superfamily

Spindlin (Spin) and Ssty were first identified for their involvement in gametogenesis. Spindlin was identified as a maternal transcript present in the unfertilised egg and early embryo, and was subsequently shown to interact with the spindle apparatus during oogenesis, and may therefore be important for mitosis . In addition, spindlin appears to be a target for cell cycle-dependent phosphorylation, and as such may play a role in cell cycle regulation during the transition from gamete to embryo . Ssty is a multi-copy, Y-linked spermatogenesis-specific transcript that appears to be required for normal spermatogenesis . Ssty may play an analogous role to spindlin in sperm cells, namely during the transition from sperm cells to early embryo, and in mitosis.

Structurally this domain superfamily comprises 14 antiparallel strands and 2 helices.
Sulfhydryl oxidase, flavin adenine dinucleotide (FAD) binding domain superfamily (QSOX_FAD-bd_sf)
Type: Homologous_superfamily

This superfamily represents a flavin adenine dinucleotide (FAD) binding domain found in Quiescin sulfhydryl oxidases (QSOX) (

). QSOX is a multi-domain disulfide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention due to its over-production in tumors. Structural studies indicate that the closure of the Trx1 domain over the FAD-binding site may enhance the active-site chemistry for disulfide formation .

Structurally, this domain consists of four helix bundle and three strands.
Ribosome-associated complex head domain superfamily (RAC_head_sf)
Type: Homologous_superfamily

The ribosome-associated complex (RAC) head domain is involved in ribosome binding . It can be found at the C terminus of the yeast Zuotin (Zuo1) protein. Zuo1 is a component of RAC, a stable ribosome-associated heterodimer that functions as a chaperone at the ribosome .

Structurally this superfamily represents a unique α-helical domain .