SII-SWORD/CoKE huggingface dataset:
G-protein coupled receptor 158/179 (GPR158/179)
Type: Family

This group includes orphan receptors GPR158, GPR158-like (also called GPR179) and similar proteins. These orphan receptors are closely related to the type B receptor for gamma-aminobutyric acid (GABA-B), which is activated by its endogenous ligand GABA, the principal inhibitory neurotransmitter . Both GPR179 and GPR158 were shown to recruit regulator of G protein signaling (RGS) complexes and thus regulate activity of other GPCRs .

GPR158 has been suggested to act as a homeostatic regulator of intraocular pressure and could be a pharmacological target for managing ocular hypertension . It has been linked to prostate cancer growth and progression . It functions in cognition, stress-induced mood control, and synaptic development and it also serves as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression . GPR158 has been recently described as metabotropic glycine receptor (mGlyR) through which glycine signals to inhibit production of the second messenger adenosine 3',5'-monophosphate . Glycine acts through this receptor and regulates neuronal excitability in cortical neurons. Structure determination of GPR158 revealed that it consists or an N-terminal extracellular domain that has a fold similar to Cache domains and a transmembrane domain, connected by a linker .
NFD6/NOXY2-like (NFD6/NOXY2-like)
Type: Family

This entry includes a group of plant proteins, including NFD6 and NOXY2 from Arabidopsis.

Protein NUCLEAR FUSION DEFECTIVE 6 (NFD6) is required for karyogamy during female gametophyte development, when the two polar nuclei fuse to form the diploid central cell nucleus .

This entry includes NONRESPONDING TO OXYLIPINS 2 (NOXY2, At5g11630) from Arabidopsis and plant homologues. NOXY2 is involved in plant defense against bacterial pathogens .
MEDAG/TEX26 (MEDAG/TEX26)
Type: Family

MEDAG/Meda-4 promotes differentiation of preadipocytes into adipocytes, and lipid accumulation and glucose uptake in mature adipocytes. It affects two major transcription regulators, Ppar-gamma2 and C/EBP-alpha, and targets genes involved in adipocyte differentiation and lipid storage. There seems to be links between Meda-4 expression and sex hormonal imbalance-induced obesity progression and metabolic alterations .

The function of TEX26 is not clear.

This entry includes a group of animal proteins, including MEDAG/TEX26.
UDP-2,3-diacylglucosamine hydrolase LpxH-like (LpxH-like)
Type: Family

LpxH (also known as YbbF) is an Escherichia coli UDP-2,3-diacylglucosamine hydrolase thought to catalyse the fourth step of lipid A biosynthesis, in which a precursor UDP-2,3-diacylglucosamine is hydrolysed to yield 2,3-diacylglucosamine 1-phosphate and UMP . YbbF belongs to the metallophosphatase (MPP) superfamily. MPPs are functionally diverse, but all share a conserved domain with an active site consisting of two metal ions (usually manganese, iron, or zinc) coordinated with octahedral geometry by a cage of histidine, aspartate, and asparagine residues.

This entry includes Escherichia coli LpxH (YbbF) and related proteins. Most of the proteins in this entry contain a metallophosphatase domain.
Tight junction-associated protein 1 domain (Tjap1_dom)
Type: Domain

This domain is found in members of the Tight junction-associated protein 1 (Tjap1) family, also known as Pilt family, a family of eukaryotic tight junction-proteins . Pilt is a component of Tight junctions (TJs) rather than Adhesin junctions (AJs). TJs function as a barrier preventing solutes and water from passing freely through the paracellular pathway. TJs consist of transmembrane proteins (claudin, occludin, and JAM) plus many peripheral membrane proteins and cell polarity molecules.

Pilt is a novel peripheral membrane protein which is incorporated into TJs after TJ strands are formed, thereby the name Pilt stands for 'protein incorporated later into TJs'. Pilt binds to the guanylate-kinase region of disk large homologue/synapse-associated protein 97 (hDlg/SAP97) .
Zinc finger BED domain-containing protein 2/3 (ZBED2/3)
Type: Family

This entry includes ZBED2 and ZBED3. The function of ZBED2 is not clear.

Zinc-finger BED domain-containing protein 3 (Zbed3) is a zinc finger protein that binds to axin and activates the Wnt/beta-catenin signalling. Interaction with axin is important for Zbed3 to inhibit beta-catenin phosphorylation, hence inhibiting beta-catenin degradation . Zbed3 has been associated with insulin resistance and type 2 diabetes mellitus in humans .
Spike glycoprotein S2 superfamily, coronavirus (S2_sf_CoV)
Type: Homologous_superfamily

The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 and S2 . The cleavage of S can occur at two distinct sites: S2 or S2' . The S1 subunit is responsible for host-receptor binding while the S2 subunit contains the membrane-fusion machinery .

Both chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active . The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail .

The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur . The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. . During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes .
Yro2-like, 7TM domain (Yro2-like_7TM)
Type: Domain

This entry represents the seven-transmembrane α-helices (TM) domain found in the yeast Yro2 protein and its closely related proteins. Although the exact function of these proteins is unknown, they show strong sequence homology to the family of microbial rhodopsins, also known as type I rhodopsins, comprising the light-driven inward chloride pump halorhodopsin (HR), the outward proton pump bacteriorhodopsin (BR) . This entry includes the Opsin-like protein carO, which is involved in the biosynthesis of neurosporaxanthin, a carboxylic apocarotenoid acting as an essential protective pigment and leading to orange pigmentation .
Peptidase C30, domain 3, coronavirus (Peptidase_C30_dom3_CoV)
Type: Homologous_superfamily

This group of cysteine peptidases correspond to MEROPS peptidase family C30 (clan PA(C)). These peptidases are related to serine endopeptidases of family S1 and are restricted to coronaviruses, where they are involved in viral polyprotein processing during replication .

This Coronavirus (CoV) domain, peptidase C30, is also known as 3C-like proteinase (3CL-pro), or CoV main protease (M-pro) domain and it is highly conserved among coronaviruses. CoV M-pro is a dimer where each subunit is composed of three domains I, II and III. Domains I and II consist of six-stranded antiparallel β barrels and together resemble the architecture of chymotrypsin, and of picornaviruses 3C proteinases. The substrate-binding site is located in a cleft between these two domains. The catalytic site is situated at the centre of the cleft. A long loop connects domain II to the C-terminal domain (domain III). This latter domain, a globular cluster of five helices, has been implicated in the proteolytic activity of M-pro. In the active site of M-pro, Cys and His form a catalytic dyad. In contrast to serine proteinases and other cysteine proteinases, which have a catalytic triad, there is no third catalytic residue present . Many drugs have been developed to inhibit CoV M-pro .

This superfamily represents CoV M-pro domain III, which is reported to be required for dimerisation and regulation . Whereas the chymotrypsin-like fold formed by domains I and II is also present in MEROPS family S1 peptidases found in plants, animals, fungi, eubacteria, archaea and viruses, the C-terminal extra helical domain III is unique for the coronavirus 3CL proteases .
Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus (NSP3_SUD-N_sf_bCoV)
Type: Homologous_superfamily

This superfamily represents the N-terminal region of the SUD domain (SUD-N or Mac2) found in non-structural protein NSP3, the product of ORF1a in group 2 (beta) coronaviruses. It is found in human SARS-CoV and SARS-CoV-2 polyprotein 1a and 1ab, and in related coronavirus polyproteins .

Non-structural protein Nsp3 contains at least seven different functional modules within its 1922-amino-acid polypeptide chain. One of these is the so-called SARS (severe acute respiratory syndrome)-unique domain (SUD), a stretch of about 338 residues that is completely absent from any other coronavirus. The SUD domain may be responsible for the high pathogenicity of the SARS coronavirus, compared to other viruses of this family . Later, the NSP3 of MHV was shown by X-ray crystallography to contain a SUD-C-like fold, so it is no longer appropriate to call this domain "SARS-unique". This region has been renamed into "Domain Preceding Ubl2 and PL2pro" (DPUP) .

SUD consists of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C . Among these, SUD-N and SUD-M are macrodomains. The SUD-N domain is a related macrodomain which also binds G-quadruplexes . While SUD-N is specific to the NSP3 of SARS and betacoronaviruses of the sarbecovirus subgenera (B lineage), SUD-M is present in most NSP3 proteins except the NSP3 from betacoronaviruses of the embecovirus subgenera (A lineage). SUD-M, despite its name, is not specific to SARS. SUD-C adopts a frataxin-like fold, has structural similarity to DNA-binding domains of DNA-modifying enzymes, binds single-stranded RNA, and regulates the RNA binding behavior of the SUD-M macrodomain. SARS-CoV Nsp3 contains a third macrodomain (the X-domain). The X-domain may function as a module binding poly(ADP-ribose); however, SUD-N and SUD-M do not bind ADP-ribose, as the triple glycine sequence involved in its binding is not conserved in these .
DNA/RNA polymerase superfamily (DNA/RNA_pol_sf)
Type: Homologous_superfamily

This entry represents the DNA/RNA polymerase superfamily, which includes DNA polymerase I, reverse transcriptase, T7 RNA polymerase, lesion bypass DNA polymerase (Y-family), RNA-dependent RNA-polymerase and dsRNA phage RNA-dependent RNA-polymerase. These enzymes share a similar protein fold at their active site, which resembles the palm subdomain of the right-hand-shaped polymerases .
Papain-like viral protease, palm and finger domains, coronavirus (PLpro_palm_finger_dom_CoV)
Type: Homologous_superfamily

In coronaviruses, papain-like protease (PL(pro)) cleaves the viral replicase polyproteins at different sites releasing non-structural protein NSP1, NSP2, NSP3, and a chymotrypsin-like protease (3CLpro) that cleaves all junctions downstream of NSP4 .

Structurally, coronaviruses papain-like protease consists of a C-terminal catalytic domain containing a right-handed fingers, palm, and thumb domain organisation as well as an N-terminal Ub-like (UBL) domain .

This superfamily represents the palm and finger domains found in papain-like protease from beta and gamma coronaviruses, respectively consisting of 8 and 5 antiparallel β-sheets in MERS-CoV and 6 and 4 antiparallel β-sheets in SARS-CoV .
Peptidase S1, PA clan, chymotrypsin-like fold (Peptidase_S1_PA_chymotrypsin)
Type: Homologous_superfamily

This entry represents the chymotrypsin-like fold found in proteins from MEROPS peptidase family S1 (clan PA). The PA clan contains both cysteine and serine proteases that can be found in plants, animals, fungi, eubacteria, archaea and viruses .

The severe acute respiratory syndrome (SARS) 3C-like protease (3CL) consists of two distinct folds, namely the N-terminal chymotrypsin fold containing domains I and II, hosting the complete catalytic machinery and the C-terminal extra helical domain III, unique for the coronavirus 3CL proteases .

The structure of a 3CL, CoV M-pro, has been solved. It is a dimer where each subunit is composed of three domains I, II and III. Domains I and II consist of six-stranded antiparallel β barrels and together resemble the architecture of chymotrypsin and of picornaviruses 3C proteinases. The substrate-binding site is located in a cleft between these two domains. The catalytic site is situated at the centre of the cleft. A long loop connects domain II to the C-terminal domain (domain III). This latter domain, a globular cluster of five helices, has been implicated in the proteolytic activity of M-pro. In the active site of M-pro, Cys and His form a catalytic dyad. In contrast to serine proteinases and other cysteine proteinases, which have a catalytic triad, there is no third catalytic residue present . Many drugs have been developed to inhibit CoV M-pro .
Nucleocapsid protein, betacoronavirus (NCAP_bCoV)
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 Betacoronavirus.
Envelope small membrane protein, betacoronavirus (E_protein_bCoV)
Type: Family

This family is specific for E proteins from betacoronaviruses.

E protein is the smallest of the major structural proteins. It is conserved among Coronavirus strains. It is an integral membrane protein involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis . During the replication cycle, E is abundantly expressed inside the infected cell, but only a small portion is incorporated into the virus envelope. The majority of the protein participates in viral assembly and budding . It can act as a viroporin by oligomerizing after insertion in host membranes to create a hydrophilic pore that allows ion transport . Additionally, the E protein is thought to prevent M protein aggregation and induce membrane curvature .

SARS-CoV E protein forms a Ca2+ permeable channel in the endoplasmic reticulum Golgi apparatus intermediate compartment (ERGIC)/Golgi membranes. The E protein ion channel activity alters Ca2+ homeostasis within cells boosting the activation of the NLRP3 inflammasome, which leads to the overproduction of IL-1beta. SARS-CoV overstimulates the NF-kappaB inflammatory pathway and interacts with the cellular protein syntenin, triggering p38 MARK activation. These signalling cascades result in exacerbated inflammation and immunopathology .

Cov E proteins have a short hydrophilic N terminus, followed by a large hydrophobic transmembrane (TM) domain, and end with a long, hydrophilic C terminus, which comprises the majority of the protein. The hydrophobic region of the TM domain contains at least one predicted amphipathic α-helix that pentamerizes to form an ion-conductive pore in membranes. CoV E proteins have been proposed to have at least two roles. One is related to their TM channel domain. This would be active in the secretory pathway, altering lumenal environments and rearranging secretory organelles and leading to efficient trafficking of virions. The other would be related to their extramembrane domains, particularly the C-terminal domain. This is involved in protein-protein interactions and targeting, among other roles .
Envelope small membrane protein, alphacoronavirus (E_protein_aCoV)
Type: Family

This family is specific for E proteins from alphacoronaviruses.

E protein is the smallest of the major structural proteins. It is conserved among Coronavirus strains. It is an integral membrane protein involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis . During the replication cycle, E is abundantly expressed inside the infected cell, but only a small portion is incorporated into the virus envelope. The majority of the protein participates in viral assembly and budding . It can act as a viroporin by oligomerizing after insertion in host membranes to create a hydrophilic pore that allows ion transport . Additionally, the E protein is thought to prevent M protein aggregation and induce membrane curvature .

SARS-CoV E protein forms a Ca2+ permeable channel in the endoplasmic reticulum Golgi apparatus intermediate compartment (ERGIC)/Golgi membranes. The E protein ion channel activity alters Ca2+ homeostasis within cells boosting the activation of the NLRP3 inflammasome, which leads to the overproduction of IL-1beta. SARS-CoV overstimulates the NF-kappaB inflammatory pathway and interacts with the cellular protein syntenin, triggering p38 MARK activation. These signalling cascades result in exacerbated inflammation and immunopathology .

Cov E proteins have a short hydrophilic N terminus, followed by a large hydrophobic transmembrane (TM) domain, and end with a long, hydrophilic C terminus, which comprises the majority of the protein. The hydrophobic region of the TM domain contains at least one predicted amphipathic α-helix that pentamerizes to form an ion-conductive pore in membranes. CoV E proteins have been proposed to have at least two roles. One is related to their TM channel domain. This would be active in the secretory pathway, altering lumenal environments and rearranging secretory organelles and leading to efficient trafficking of virions. The other would be related to their extramembrane domains, particularly the C-terminal domain. This is involved in protein-protein interactions and targeting, among other roles .
Brdt, bromodomain, repeat I (Bromo_Brdt_I)
Type: Domain

Human Brdt is a testis-specific member of the BET subfamily of bromodomain proteins. The BET proteins contain two bromodomains and a region of homology in the C-terminal region, designated the extra terminal (ET) motif. The first bromodomain in Brdt has been shown to be essential for male germ cell differentiation . Bromodomains are 110 amino acid long domains, that are found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine .

This entry represents the first bromodomain found in Brdt and related proteins.
Brdt, bromodomain, repeat II (Bromo_Brdt_II)
Type: Domain

Human Brdt is a testis-specific member of the BET subfamily of bromodomain proteins. The BET proteins contain two bromodomains and a region of homology in the C-terminal region, designated the extra terminal (ET) motif. The first bromodomain in Brdt has been shown to be essential for male germ cell differentiation . Bromodomains are 110 amino acid long domains, that are found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine .

This entry represents the second bromodomain found in Brdt and related proteins.