SII-SWORD/CoKE huggingface dataset:
Envelope small membrane protein, SARS-CoV-2-like (E_SARS-CoV-2)
Type: Family

This entry represents the Envelope (E) small membrane protein of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV) or COVID-19 virus.

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 .
Spike (S) protein S1 subunit, receptor-binding domain, HKU4-like (Spike_S1_RBD_HKU4-like)
Type: Domain

This entry represents the receptor-binding domain (RBD) of the S1 subunit of the spike (S) protein from Tylonycteris bat coronavirus HKU4 and other Middle East Respiratory Syndrome (MERS)-related coronaviruses which are phylogenetically closely related, sharing high sequence similarity. HKU4 is able to bind the MERS-CoV receptor, human dipeptidyl peptidase 4 (DPP4), also called CD26 but with lower affinity than MERS-CoV which indicates that HKU4 is less adapted to human DPP4 .

The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface .
Envelope small membrane protein, MERS-CoV-like (E_MERS-CoV-like)
Type: Family

This entry represents the Envelope (E) small membrane protein of Middle East respiratory syndrome (MERS) coronavirus (CoV), as well as E proteins from related coronaviruses.

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 .
Spike (S) protein S1 subunit, receptor-binding domain, HEV (Spike_S1_RBD_HEV)
Type: Domain

The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface .

This entry represents the receptor-binding domain (RDB) of the Spike protein S1 subunit from the porcine hemagglutinating encephalomyelitis virus (HEV), which is related to SARS and MERS betacoronaviruses and is associated with acute outbreaks of wasting and encephalitis in nursing piglets from pig farms. Porcine HEV uses 9-O-acetyl-sialic acid (9-O-Ac-Sia) as a receptor, like the closely related HCoV-OC43 and HCoV-HKU1 viruses .
NSP3, DPUP domain, murine hepatitis virus-like (NSP3_DPUP_MHV)
Type: Domain

This entry represents the DPUP (domain preceding Ubl2 and PLP2) of murine hepatitis virus (MHV) non-structural protein 3 (NSP3) and other NSP3s from betacoronaviruses in the embecovirus subgenera (A lineage), including human CoV OC43, rabbit CoV HKU14 and porcine hemagglutinating encephalomyelitis virus (HEV), among others.

MHV NSP3 contains a DPUP that is located N-terminal to the ubiquitin-like domain 2 (Ubl2) and papain-like protease 2 (PLP2) catalytic domain. It is structurally similar to the Severe Acute Respiratory Syndrome (SARS) CoV unique domain C (SUD-C), adopting a frataxin-like fold that has structural similarity to DNA-binding domains of DNA-modifying enzymes. SUD-C is also located N-terminal to Ubl2 and PLP2 in SARS NSP3, similar to the DPUP of MHV NSP3; however, unlike DPUP, it is preceded by SUD-N and SUD-M macrodomains that are absent in MHV NSP3. Though structurally similar, there is little sequence similarity between DPUP and SUD-C. SARS SUD-C has been shown to bind to single-stranded RNA and recognize purine bases more strongly than pyrimidine bases; it also regulates the RNA binding behavior of the SARS SUD-M macrodomain. It is not known whether DPUP functions in the same way .
NSP3, SUD-C domain, MERS-CoV-like (NSP3_SUD_C_MERS-CoV)
Type: Domain

This entry represents the SUD-C of Middle East respiratory syndrome-related (MERS) coronavirus (CoV) NSP3 and other NSP3s from betacoronaviruses in the merbecovirus subgenera (C lineage), including several bat-CoVs such as Tylonycteris bat CoV HKU4, Pipistrellus bat CoV HKU5, and Hypsugo bat CoV HKU25.

NSP3 of SARS coronavirus includes a SARS-unique domain (SUD) consisting of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C. SUD-N and SUD-M are macro domains which bind G-quadruplexes (unusual nucleic-acid structures formed by consecutive guanosine nucleotides) . SUD is not as specific to SARS CoV as originally thought and is also found in MERS and related bat coronaviruses. Similar to SARS SUD-C, Tylonycteris bat-CoV HKU4 SUD-C (HKU4 C), a member of the MERS SUD-C group, also adopts a frataxin-like fold that has structural similarity to DNA-binding domains of DNA-modifying enzymes. However, there is little sequence similarity between the two domains. SARS SUD-C has been shown to bind to single-stranded RNA and recognise purine bases more strongly than pyrimidine bases; it also regulates the RNA binding behaviour of the SARS SUD-M macrodomain. It is not known whether MERS SUD-C or HKU4 C functions in the same way .
Non-structural protein 2, IBV-like (NSP2_IBV-like)
Type: Domain

Avian infectious bronchitis virus (IBV) is a gammacoronavirus that belongs to Group III of coronaviruses. As all coronaviruses, they have a large genome containing the replicase gene consisting of two large ORFs, ORF1a and 1b that encode two replicase polyproteins ppa1a/1ab, which are then autoproteolytically processed into 15 or 16 matured nonstructural proteins to achieve viral genomic replication, assembly and maturation. This group contains avian viruses and differs from the other groups in that they do not encode the essential pathogenic factor nonstructural protein 1 (NSP1) and instead start with NSP2. IBV NSP2 is one of the first replicase proteins to be translated and processed in the viral life cycle . NSP2 is a weak protein kinase R (PKR) antagonist, which may suggest that it plays a role in interfering with intracellular immunity .

This entry represents the nonstructural protein 2 (NSP2) from Avian infectious bronchitis virus (IBV) and related viruses which belong to gamma and deltacoronaviruses genera.
Non-structural protein 2, MHV-like (NSP2_MHV-like)
Type: Domain

The functions of NSP2 remain unclear. SARS-CoV NSP2, rather than playing a role in viral replication, may be involved in altering the host cell environment; deletion of NSP2 from the SARS-CoV genome results in only a modest reduction in viral titers, and it has been shown to interact with two host proteins, prohibitin 1 (PHB1) and PHB2 which have been implicated in cellular functions, including cell-cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis . MHV NSP2, also known as p65, different from SARS-CoV NSP2, may play an important role in the viral life cycle .

This entry represents NSP2 from Murine hepatitis virus (MHV) and betacoronaviruses in the embecovirus subgenera (A lineage).
Nonstructural protein 2, HCoV-229E-like (NSP2_HCoV-229E-like)
Type: Domain

This entry represents NSP2 from alphacoronavirus, including human coronavirus 229E (HCoV-229E), Porcine epidemic diarrhea virus and related viruses .

The functions of NSP2 remain unclear. SARS-CoV NSP2, rather than playing a role in viral replication, may be involved in altering the host cell environment; deletion of NSP2 from the SARS-CoV genome results in only a modest reduction in viral titers, and it has been shown to interact with two host proteins, prohibitin 1 (PHB1) and PHB2 which have been implicated in cellular functions, including cell-cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis . MHV NSP2, also known as p65, different from SARS-CoV NSP2, may play an important role in the viral life cycle .
Non-structural protein 2, bat coronavirus HKU9-like (NSP2_HKU9-like)
Type: Domain

This entry includes NSP2 from Rousettus bat coronavirus HKU9 and betacoronaviruses in the nobecovirus subgenera (D lineage).

The functions of NSP2 remain unclear. SARS-CoV NSP2, rather than playing a role in viral replication, may be involved in altering the host cell environment; deletion of NSP2 from the SARS-CoV genome results in only a modest reduction in viral titers, and it has been shown to interact with two host proteins, prohibitin 1 (PHB1) and PHB2 which have been implicated in cellular functions, including cell-cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis . MHV NSP2, also known as p65, different from SARS-CoV NSP2, may play an important role in the viral life cycle .
Non-structural protein 2, MERS-CoV-like (NSP2_MERS-like)
Type: Domain

The functions of NSP2 remain unclear. SARS-CoV NSP2, rather than playing a role in viral replication, may be involved in altering the host cell environment; deletion of NSP2 from the SARS-CoV genome results in only a modest reduction in viral titers, and it has been shown to interact with two host proteins, prohibitin 1 (PHB1) and PHB2 which have been implicated in cellular functions, including cell-cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis . MHV NSP2, also known as p65, different from SARS-CoV NSP2, may play an important role in the viral life cycle .

This entry represents NSP2 from Middle East respiratory syndrome-related coronavirus (MERS-CoV) and betacoronaviruses in the merbecovirus subgenera (C lineage).
Non-structural protein 2, SARS-CoV-like (NSP2_SARS-CoV-like)
Type: Domain

The functions of NSP2 remain unclear. SARS-CoV NSP2, rather than playing a role in viral replication, may be involved in altering the host cell environment; deletion of NSP2 from the SARS-CoV genome results in only a modest reduction in viral titers, and it has been shown to interact with two host proteins, prohibitin 1 (PHB1) and PHB2 which have been implicated in cellular functions, including cell-cycle progression, cell migration, cellular differentiation, apoptosis, and mitochondrial biogenesis . MHV NSP2, also known as p65, different from SARS-CoV NSP2, may play an important role in the viral life cycle .

This entry represents non-structural protein 2 (NSP2) from Severe acute respiratory syndrome coronavirus (SARS-CoV) and betacoronaviruses in the sarbecovirus subgenera (B lineage). In SARS-CoV-2, this protein coopts the GIGYF2/4EHP complex, which suppresses IFN-beta and, therefore, leads to evasion of a cellular innate immune response .
Structural accessory protein ORF7a, SARS-CoV-2-like (ORF7a_SARS-CoV-2-like)
Type: Family

SARS-CoV contains a number of open reading frames that code for a total of eight accessory proteins, namely ORFs 3a, 3b, 6, 7a, 7b, 8a, 8b, and 9b. These ORFs are specific for SARS-CoV and do not show significant homology to accessory proteins of other coronaviruses. This entry represents the structural accessory protein ORF7a, also called NS7a, of Severe Acute Respiratory Syndrome Coronaviruses (SARS-CoV) from betacoronavirus subgenera Sarbecovirus (lineage B), including SARS-CoV-2. ORF7a/NS7a from betacoronavirus in the subgenera Sarbecovirus (B lineage) are not related to NS7a proteins from other coronavirus lineages.

Structurally, ORF7a possesses a distinctive immunoglobulin (Ig)-like domain which is related to extracellular metazoan Ig domains that are involved in adhesion, such as ICAM; it also contains a 15-aa signal peptide sequence at its N terminus, an 81-aa luminal domain, a 21-aa transmembrane domain, and a short C-terminal tail. Coexpression of SARS-CoV ORF7a with S, M, N, and E proteins resulted in production of virus-like particles (VLPs) carrying ORF7a protein, indicating that ORF7a is a viral structural protein. Expression studies of ORF7a have shown that biological functions include induction of apoptosis through a caspase-dependent pathway, activation of the p38 mitogen-activated protein kinase signaling pathway, inhibition of host protein translation, and suppression of cell growth progression. These results collectively suggested that ORF7a protein may be involved in virus-host interactions . Studies in SARS-CoV-2 revealed that ORF7a plays a role as antagonist of host tetherin (BST2), disrupting its antiviral effect. ORF7a binds to BST2 and sequesters it to the perinuclear region, thereby preventing its antiviral function at cell membrane .
ORF8, SARS-CoV-2 (ORF8_SARS-CoV-2-like)
Type: Family

This entry represents the ORF8 immunoglobulin (Ig) domain protein of Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2, also known as a 2019 novel coronavirus, 2019-nCoV) and related Sarbecovirus ORF8 proteins.

ORF8 is an accessory protein that is not shared by all members of subgenus sarbecovirus. The presence and location of ORF8 in the SARS-CoV-2 genome has led its classification with SARS-CoV . ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts . ORF8 has been suggested to be one of the relevant genes in the study of human adaptation of the virus .

The ORF8 protein is a fast-evolving protein in SARS-related CoVs, with a tendency to recombine and undergo deletions. During the early phases of the SARS (SARS-CoV) epidemic in 2002, human isolates were found to possess a unique continuous ORF8 with 366 nucleotides and a predicted protein with 122 amino acids. During the middle and late phases of the SARS epidemic, two functional ORFs (ORF8a and ORF8b) were emerged; they are predicted to encode two small proteins, 8a with 39 amino acids and 8b with 84 amino acids. Interestingly, SARS-CoV-2 ORF8 has not undergone any significantly measurable deletion events, so its function as a full-length protein might be more important to its pathogenicity . ORF8 plays a role in modulating host immune response which may act by down-regulating major histocompatibility complex class I (MHC-I) . It may inhibit expression of some members of the IFN-stimulated gene (ISG) family including hosts IGF2BP1/ZBP1, MX1 and MX2, and DHX58 . ORF8 also binds to IL17RA receptor, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors, contributing to cytokine storm during COVID-19 infection .
ORF8, bat coronavirus Rf1-like (ORF8_Bat_SARS_CoV_Rf1-like)
Type: Family

This subfamily includes the ORF8 immunoglobulin (Ig) domain proteins of bat coronavirus Rf1 (Bat SARS CoV Rf1) and Bat CoV 273/2005, which have been classified previously as type II ORF8 proteins.

ORF8 is an accessory protein that is not shared by all members of subgenus sarbecovirus. The presence and location of ORF8 in the SARS-CoV-2 genome has led its classification with SARS-CoV . ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts . ORF8 has been suggested to be one of the relevant genes in the study of human adaptation of the virus .

The ORF8 protein is a fast-evolving protein in SARS-related CoVs, with a tendency to recombine and undergo deletions. During the early phases of the SARS (SARS-CoV) epidemic in 2002, human isolates were found to possess a unique continuous ORF8 with 366 nucleotides and a predicted protein with 122 amino acids. During the middle and late phases of the SARS epidemic, two functional ORFs (ORF8a and ORF8b) were emerged; they are predicted to encode two small proteins, 8a with 39 amino acids and 8b with 84 amino acids. Interestingly, SARS-CoV-2 ORF8 has not undergone any significantly measurable deletion events, so its function as a full-length protein might be more important to its pathogenicity . ORF8 plays a role in modulating host immune response which may act by down-regulating major histocompatibility complex class I (MHC-I) . It may inhibit expression of some members of the IFN-stimulated gene (ISG) family including hosts IGF2BP1/ZBP1, MX1 and MX2, and DHX58 . ORF8 also binds to IL17RA receptor, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors, contributing to cytokine storm during COVID-19 infection .
ORF8, bat SARS coronavirus HKU3-1-like (ORF8_bat_SARS-CoV_HKU3-1-like)
Type: Family

This entry includes the ORF8 immunoglobulin (Ig) domain proteins of Bat SARS coronavirus HKU3-1, which have been classified previously as type III ORF8's.

ORF8 is an accessory protein that is not shared by all members of subgenus sarbecovirus. The presence and location of ORF8 in the SARS-CoV-2 genome has led its classification with SARS-CoV . ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts . ORF8 has been suggested to be one of the relevant genes in the study of human adaptation of the virus .

The ORF8 protein is a fast-evolving protein in SARS-related CoVs, with a tendency to recombine and undergo deletions. During the early phases of the SARS (SARS-CoV) epidemic in 2002, human isolates were found to possess a unique continuous ORF8 with 366 nucleotides and a predicted protein with 122 amino acids. During the middle and late phases of the SARS epidemic, two functional ORFs (ORF8a and ORF8b) were emerged; they are predicted to encode two small proteins, 8a with 39 amino acids and 8b with 84 amino acids. Interestingly, SARS-CoV-2 ORF8 has not undergone any significantly measurable deletion events, so its function as a full-length protein might be more important to its pathogenicity . ORF8 plays a role in modulating host immune response which may act by down-regulating major histocompatibility complex class I (MHC-I) . It may inhibit expression of some members of the IFN-stimulated gene (ISG) family including hosts IGF2BP1/ZBP1, MX1 and MX2, and DHX58 . ORF8 also binds to IL17RA receptor, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors, contributing to cytokine storm during COVID-19 infection .