UniProt functional annotation for P0DTC2



	UniProt functional annotation for P0DTC2

UniProt code: P0DTC2.

Organism: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).

Taxonomy: Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes; Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae; Betacoronavirus; Sarbecovirus.

Function: [Spike protein S1]: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32221306, PubMed:32075877, PubMed:32155444). Binding to host NRP1 and NRP2 via C-terminal polybasic sequence enhances virion entry into host cell (PubMed:33082294, PubMed:33082293). This interaction may explain virus tropism of human olfactory epithelium cells, which express high level of NRP1 and NRP2 but low level of ACE2 (PubMed:33082293). The stalk domain of S contains three hinges, giving the head unexpected orientational freedom (PubMed:32817270). Uses human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Can be alternatively processed by host furin (PubMed:32362314). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes. {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32142651, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:32817270, ECO:0000269|PubMed:33082293, ECO:0000269|PubMed:33082294, ECO:0000303|PubMed:33082293}.

Function: [Spike protein S2]: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of- hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. {ECO:0000255|HAMAP-Rule:MF_04099}.

Function: [Spike protein S2']: Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis. {ECO:0000255|HAMAP-Rule:MF_04099}.

Function: [Spike glycoprotein]: May down-regulate host tetherin (BST2) by lysosomal degradation, thereby counteracting its antiviral activity. {ECO:0000250|UniProtKB:P59594}.

Subunit: [Spike glycoprotein]: Homotrimer; each monomer consists of a S1 and a S2 subunit (PubMed:32075877, PubMed:32155444, PubMed:32245784). The resulting peplomers protrude from the virus surface as spikes (PubMed:32979942). Interacts with ORF3a protein and ORF7a protein (By similarity) (PubMed:32075877, PubMed:32155444, PubMed:32245784, PubMed:32979942). There are an average of 26 +/-15 spike trimers at the surface of virion particles (PubMed:32979942). {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32245784, ECO:0000269|PubMed:32979942}.

Subunit: [Spike protein S1]: Binds to host ACE2 (PubMed:32221306, PubMed:33607086, PubMed:32075877, PubMed:32132184, PubMed:32155444, PubMed:32225175, PubMed:32225176). RBD also interacts with the N-linked glycan on Asn90 of ACE2 (PubMed:33607086). Cleavage of S generates a polybasic C-terminal sequence on S1 that binds to host Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors (PubMed:33082294, PubMed:33082293). Interacts with host integrin alpha-5/beta-1 (ITGA5:ITGB1) and with ACE2 in complex with integrin alpha-5/beta-1 (ITGA5:ITGB1) (PubMed:33102950). May interact via cytoplasmic c- terminus with M protein (PubMed:33229438). {ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32132184, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32225175, ECO:0000269|PubMed:32225176, ECO:0000269|PubMed:33082293, ECO:0000269|PubMed:33082294, ECO:0000269|PubMed:33102950, ECO:0000269|PubMed:33229438, ECO:0000269|PubMed:33607086}.

Subcellular location: Virion membrane {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32979942}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099}. Host endoplasmic reticulum-Golgi intermediate compartment membrane {ECO:0000255|HAMAP-Rule:MF_04099}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099}. Host cell membrane {ECO:0000255|HAMAP-Rule:MF_04099}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099}. Note=Accumulates in the endoplasmic reticulum-Golgi intermediate compartment, where it participates in virus particle assembly. Colocalizes with S in the host endoplasmic reticulum-Golgi intermediate compartment. Some S oligomers are transported to the host plasma membrane, where they may mediate cell-cell fusion (By similarity). An average of 26 +/-15 S trimers are found randomly distributed at the surface of the virion (PubMed:32979942). {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32979942}.

Domain: The KxHxx motif seems to function as an ER retrieval and binds COPI in vitro. {ECO:0000250|UniProtKB:P59594}.

Domain: Fusion peptide 1 (FP1) and fusion peptide 2 (FP2) function cooperatively and have a membrane-ordering effect on lipid headgroups and shallow hydrophobic regions of target bilayers. They are considered as two domains of an extended, bipartite FP. The membrane-ordering activity is calcium-dependent and also dependent on correct folding, which is maintained by an internal disulfide bond in FP2. {ECO:0000255|HAMAP-Rule:MF_04099}.

Ptm: The cytoplasmic Cys-rich domain is palmitoylated. Spike glycoprotein is digested within host endosomes. {ECO:0000255|HAMAP- Rule:MF_04099}.

Ptm: Specific enzymatic cleavages in vivo yield mature proteins. The precursor is processed into S1 and S2 by host CTSL, TMPRSS2 or furin to yield the mature S1 and S2 proteins (PubMed:32155444). CTSL cleavage would occur in endosomes (PubMed:32221306, PubMed:33465165). TMPRSS2 cleavage would occur at the cell surface, allowing the virus to enter the cell despite inhibition of the endosomal pathway by hydroxychloroquine (PubMed:33465165). In addition, a second cleavage results in the release of a fusion peptide upon viral binding to the host cell receptor (By similarity). The polybasic furin cleavage site is absent in SARS-CoV S (PubMed:32155444, PubMed:32362314, PubMed:33465165). It increases the dependence on TMPRSS2 expression by SARS-CoV-2 (PubMed:33465165). {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:33465165}.

Ptm: Highly decorated by heterogeneous N-linked glycans protruding from the trimer surface (PubMed:32075877, PubMed:32155444, PubMed:32929138). Highly glycosylated by host both on S1 and S2 subunits, occluding many regions across the surface of the protein (PubMed:32366695, PubMed:32363391, PubMed:32929138). Approximately 40% of the protein surface is shielded from antibody recognition by glycans, with the notable exception of the ACE2 receptor binding domain (PubMed:32929138). {ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32363391, ECO:0000269|PubMed:32366695, ECO:0000269|PubMed:32929138}.

Polymorphism: Variant B.1.1.7 belongs to a lineage isolated first in United Kingdom (Dec 2020). It is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, 501Y.V1 or 20B/501Y.V1. {ECO:0000305|PubMed:33413740}.

Polymorphism: Variant 501Y.V2 belongs to a lineage first isolated in South Africa (Dec 2020) is also called B 1.351. {ECO:0000305}.

Miscellaneous: Variant D614G has become the most prevalent circulating sequence in the global pandemic since april 2020 (PubMed:32697968). The mutation is associated with higher viral loads produced in cell culture and animal models (PubMed:32697968, PubMed:33106671, PubMed:33184236). It would not change pathogenicity nor neutralization properties vs vaccination (PubMed:33184236). May be prevalent because the mutation increases virus transmission in human population (PubMed:33106671). {ECO:0000269|PubMed:32697968, ECO:0000269|PubMed:33106671, ECO:0000269|PubMed:33184236}.

Similarity: Belongs to the betacoronaviruses spike protein family. {ECO:0000255|HAMAP-Rule:MF_04099}.

Annotations taken from UniProtKB at the EBI.


Organism:		Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).
Taxonomy:		Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes; Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae; Betacoronavirus; Sarbecovirus.



Function:		[Spike protein S1]: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32221306, PubMed:32075877, PubMed:32155444). Binding to host NRP1 and NRP2 via C-terminal polybasic sequence enhances virion entry into host cell (PubMed:33082294, PubMed:33082293). This interaction may explain virus tropism of human olfactory epithelium cells, which express high level of NRP1 and NRP2 but low level of ACE2 (PubMed:33082293). The stalk domain of S contains three hinges, giving the head unexpected orientational freedom (PubMed:32817270). Uses human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Can be alternatively processed by host furin (PubMed:32362314). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes. {ECO:0000255\|HAMAP-Rule:MF_04099, ECO:0000269\|PubMed:32075877, ECO:0000269\|PubMed:32142651, ECO:0000269\|PubMed:32155444, ECO:0000269\|PubMed:32221306, ECO:0000269\|PubMed:32362314, ECO:0000269\|PubMed:32817270, ECO:0000269\|PubMed:33082293, ECO:0000269\|PubMed:33082294, ECO:0000303\|PubMed:33082293}.



Function:		[Spike protein S2]: mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of- hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. {ECO:0000255\|HAMAP-Rule:MF_04099}.



Function:		[Spike protein S2']: Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis. {ECO:0000255\|HAMAP-Rule:MF_04099}.



Function:		[Spike glycoprotein]: May down-regulate host tetherin (BST2) by lysosomal degradation, thereby counteracting its antiviral activity. {ECO:0000250\|UniProtKB:P59594}.


Subunit:		[Spike glycoprotein]: Homotrimer; each monomer consists of a S1 and a S2 subunit (PubMed:32075877, PubMed:32155444, PubMed:32245784). The resulting peplomers protrude from the virus surface as spikes (PubMed:32979942). Interacts with ORF3a protein and ORF7a protein (By similarity) (PubMed:32075877, PubMed:32155444, PubMed:32245784, PubMed:32979942). There are an average of 26 +/-15 spike trimers at the surface of virion particles (PubMed:32979942). {ECO:0000255\|HAMAP-Rule:MF_04099, ECO:0000269\|PubMed:32075877, ECO:0000269\|PubMed:32155444, ECO:0000269\|PubMed:32245784, ECO:0000269\|PubMed:32979942}.
Subunit:		[Spike protein S1]: Binds to host ACE2 (PubMed:32221306, PubMed:33607086, PubMed:32075877, PubMed:32132184, PubMed:32155444, PubMed:32225175, PubMed:32225176). RBD also interacts with the N-linked glycan on Asn90 of ACE2 (PubMed:33607086). Cleavage of S generates a polybasic C-terminal sequence on S1 that binds to host Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors (PubMed:33082294, PubMed:33082293). Interacts with host integrin alpha-5/beta-1 (ITGA5:ITGB1) and with ACE2 in complex with integrin alpha-5/beta-1 (ITGA5:ITGB1) (PubMed:33102950). May interact via cytoplasmic c- terminus with M protein (PubMed:33229438). {ECO:0000269\|PubMed:32075877, ECO:0000269\|PubMed:32132184, ECO:0000269\|PubMed:32155444, ECO:0000269\|PubMed:32221306, ECO:0000269\|PubMed:32225175, ECO:0000269\|PubMed:32225176, ECO:0000269\|PubMed:33082293, ECO:0000269\|PubMed:33082294, ECO:0000269\|PubMed:33102950, ECO:0000269\|PubMed:33229438, ECO:0000269\|PubMed:33607086}.
Subcellular location:		Virion membrane {ECO:0000255\|HAMAP-Rule:MF_04099, ECO:0000269\|PubMed:32979942}; Single-pass type I membrane protein {ECO:0000255\|HAMAP-Rule:MF_04099}. Host endoplasmic reticulum-Golgi intermediate compartment membrane {ECO:0000255\|HAMAP-Rule:MF_04099}; Single-pass type I membrane protein {ECO:0000255\|HAMAP-Rule:MF_04099}. Host cell membrane {ECO:0000255\|HAMAP-Rule:MF_04099}; Single-pass type I membrane protein {ECO:0000255\|HAMAP-Rule:MF_04099}. Note=Accumulates in the endoplasmic reticulum-Golgi intermediate compartment, where it participates in virus particle assembly. Colocalizes with S in the host endoplasmic reticulum-Golgi intermediate compartment. Some S oligomers are transported to the host plasma membrane, where they may mediate cell-cell fusion (By similarity). An average of 26 +/-15 S trimers are found randomly distributed at the surface of the virion (PubMed:32979942). {ECO:0000255\|HAMAP-Rule:MF_04099, ECO:0000269\|PubMed:32979942}.
Domain:		The KxHxx motif seems to function as an ER retrieval and binds COPI in vitro. {ECO:0000250\|UniProtKB:P59594}.
Domain:		Fusion peptide 1 (FP1) and fusion peptide 2 (FP2) function cooperatively and have a membrane-ordering effect on lipid headgroups and shallow hydrophobic regions of target bilayers. They are considered as two domains of an extended, bipartite FP. The membrane-ordering activity is calcium-dependent and also dependent on correct folding, which is maintained by an internal disulfide bond in FP2. {ECO:0000255\|HAMAP-Rule:MF_04099}.
Ptm:		The cytoplasmic Cys-rich domain is palmitoylated. Spike glycoprotein is digested within host endosomes. {ECO:0000255\|HAMAP- Rule:MF_04099}.
Ptm:		Specific enzymatic cleavages in vivo yield mature proteins. The precursor is processed into S1 and S2 by host CTSL, TMPRSS2 or furin to yield the mature S1 and S2 proteins (PubMed:32155444). CTSL cleavage would occur in endosomes (PubMed:32221306, PubMed:33465165). TMPRSS2 cleavage would occur at the cell surface, allowing the virus to enter the cell despite inhibition of the endosomal pathway by hydroxychloroquine (PubMed:33465165). In addition, a second cleavage results in the release of a fusion peptide upon viral binding to the host cell receptor (By similarity). The polybasic furin cleavage site is absent in SARS-CoV S (PubMed:32155444, PubMed:32362314, PubMed:33465165). It increases the dependence on TMPRSS2 expression by SARS-CoV-2 (PubMed:33465165). {ECO:0000255\|HAMAP-Rule:MF_04099, ECO:0000269\|PubMed:32155444, ECO:0000269\|PubMed:32221306, ECO:0000269\|PubMed:32362314, ECO:0000269\|PubMed:33465165}.
Ptm:		Highly decorated by heterogeneous N-linked glycans protruding from the trimer surface (PubMed:32075877, PubMed:32155444, PubMed:32929138). Highly glycosylated by host both on S1 and S2 subunits, occluding many regions across the surface of the protein (PubMed:32366695, PubMed:32363391, PubMed:32929138). Approximately 40% of the protein surface is shielded from antibody recognition by glycans, with the notable exception of the ACE2 receptor binding domain (PubMed:32929138). {ECO:0000269\|PubMed:32075877, ECO:0000269\|PubMed:32155444, ECO:0000269\|PubMed:32363391, ECO:0000269\|PubMed:32366695, ECO:0000269\|PubMed:32929138}.
Polymorphism:		Variant B.1.1.7 belongs to a lineage isolated first in United Kingdom (Dec 2020). It is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, 501Y.V1 or 20B/501Y.V1. {ECO:0000305\|PubMed:33413740}.
Polymorphism:		Variant 501Y.V2 belongs to a lineage first isolated in South Africa (Dec 2020) is also called B 1.351. {ECO:0000305}.
Miscellaneous:		Variant D614G has become the most prevalent circulating sequence in the global pandemic since april 2020 (PubMed:32697968). The mutation is associated with higher viral loads produced in cell culture and animal models (PubMed:32697968, PubMed:33106671, PubMed:33184236). It would not change pathogenicity nor neutralization properties vs vaccination (PubMed:33184236). May be prevalent because the mutation increases virus transmission in human population (PubMed:33106671). {ECO:0000269\|PubMed:32697968, ECO:0000269\|PubMed:33106671, ECO:0000269\|PubMed:33184236}.
Similarity:		Belongs to the betacoronaviruses spike protein family. {ECO:0000255\|HAMAP-Rule:MF_04099}.