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FUNCTION Attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. The major receptor is host ACE2 (PubMed:32142651, PubMed:32155444, PubMed:33607086). When S2/S2' has been cleaved, binding to the receptor triggers direct fusion at the cell membrane (PubMed:34561887). When S2/S2' has not been cleaved, binding to the receptor results in internalization of the virus by endocytosis using host TFRC and GRM2 and leading to fusion of the virion membrane with the host endosomal membrane (PubMed:32075877, PubMed:32221306, PubMed:34903715, PubMed:36779763). Alternatively, may use NRP1/NRP2 (PubMed:33082294, PubMed:33082293) and integrin as entry receptors (PubMed:35150743). The use of NRP1/NRP2 receptors may explain the tropism of the virus in human olfactory epithelial cells, which express these molecules at high levels but ACE2 at low levels (PubMed:33082293). Uses also ASGR1 as an alternative receptor in an ACE2-independent manner (PubMed:34837059). The stalk domain of S contains three hinges, giving the head unexpected orientational freedom (PubMed:32817270).FUNCTION Precursor of the fusion protein processed in the biosynthesis of the S protein and the formation of virus particle. Mediates fusion of the virion and cellular membranes by functioning as a class I viral fusion protein. Contains two viral fusion peptides that are unmasked after cleavage. The S2/S2' cleavage occurs during virus entry at the cell membrane by host TMPRSS2 (PubMed:32142651) or during endocytosis by host CSTL (PubMed:32703818, PubMed:34159616). In either case, this triggers an extensive and irreversible conformational change leading to fusion of the viral envelope with the cellular cytoplasmic membrane, releasing viral genomic RNA into the host cell cytoplasm (PubMed:34561887). 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 fusion of the viral and target cell membranes, the coiled coil regions (heptad repeats) adopt a trimer-of-hairpins structure and position the fusion peptide in close proximity to the C-terminal region of the ectodomain. Formation of this structure appears to promote apposition and subsequent fusion of viral and target cell membranes.FUNCTION Subunit of the fusion protein that is processed upon entry into the host cell. Mediates fusion of the virion and cellular membranes by functioning as a class I viral fusion protein. Contains a viral fusion peptide that is unmasked after S2 cleavage. This cleavage can occur at the cell membrane by host TMPRSS2 or during endocytosis by host CSTL (PubMed:32703818, PubMed:34159616). In either case, this triggers an extensive and irreversible conformational change that leads to fusion of the viral envelope with the cellular cytoplasmic membrane, releasing viral genomic RNA into the host cell cytoplasm (PubMed:34561887). 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 fusion of the viral and target cell membranes, the coiled coil regions (heptad repeats) adopt a trimer-of-hairpins structure and position the fusion peptide in close proximity to the C-terminal region of the ectodomain. Formation of this structure appears to promote apposition and subsequent fusion of viral and target cell membranes.SUBUNIT 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). Binds to host MBL2 (PubMed:35102342). This binding occurs via glycans and inhibits viral infectivity. Inhibition is effective against alpha, beta, gamma, and delta variants (PubMed:35102342). Interacts with host TFRC; this interaction plays a role in virus internalization (PubMed:36779763). Interacts with host GRM2; this interaction plays a role in virus internalization (PubMed:34903715). Interacts with host ASGR1 (PubMed:34837059).SUBUNIT Binds to host ACE2 (PubMed:32075877, PubMed:32132184, PubMed:32155444, PubMed:32221306, PubMed:32225175, PubMed:32225176, PubMed:33607086). RBD also interacts with the N-linked glycan on 'Asn-90' 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:33082293, PubMed:33082294). 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). May interact (via N-terminus) with host bilirubin and biliverdin, thereby preventing antibody binding to the SARS-CoV-2 spike NTD via an allosteric mechanism (PubMed:33888467). May interact with host LRRC15, thereby allowing attachment to host cells (PubMed:36735681).INTERACTION Accumulates in the endoplasmic reticulum-Golgi intermediate compartment, where it participates in virus particle assembly. Some S oligomers are transported to the host plasma membrane, where they may mediate cell-cell fusion (PubMed:34504087). An average of 26 +/-15 S trimers are found randomly distributed at the surface of the virion (PubMed:32979942).DOMAIN Contains sequence and structural motifs very similar to those of a bacterial superantigen and can directly bind and activate T-cell receptors. Activation of a broad T-cell repertoire may be involved in the hyperinflammatory syndrome in acute COVID disease.DOMAIN The KxHxx motif seems to function as an ER retrieval and binds COPI in vitro.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.PTM The cytoplasmic Cys-rich domain is palmitoylated. Palmitoylated spike proteins drive the formation of localized ordered cholesterol and sphingo-lipid-rich lipid nanodomains in the early Golgi, where viral budding occurs.PTM Specific enzymatic cleavages in vivo yield mature proteins. The precursor is processed into S1 and S2 by host furin or unknown proteases to yield the mature S1 and S2 proteins (PubMed:32155444, PubMed:32362314, PubMed:32703818, PubMed:34159616, PubMed:34561887). Processing between S2 and S2' occurs either by host CTSL in endosomes (PubMed:32221306, PubMed:33465165, PubMed:34159616), or by host TMPRSS2 at the cell surface (PubMed:32142651). Both cleavages are necessary for the protein to be fusion competent (PubMed:32703818, PubMed:34159616, PubMed:34561887). Cell surface activation allows the virus to enter the cell despite inhibition of the endosomal pathway by hydroxychloroquine (PubMed:33465165). 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). D614G substitution would enhance furin cleavage at the S1/S2 junction (PubMed:33417835).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:32363391, PubMed:32366695, 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).PTM O-glycosylated by host GALNT1 at the end of S1. This could reduce the efficiency of S1/S2 cleavage.POLYMORPHISM Variant Alpha/B.1.1.7 belongs to a lineage isolated first in United Kingdom (December 2020). It is also called Variant of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, 501Y.V1 or 20B/501Y.V1 (PubMed:33413740). It has an estimated 25% increase of transmissibility (PubMed:34142653).POLYMORPHISM Variant Beta/B.1.351 belongs to a lineage first isolated in South Africa (December 2020) and is also called 501Y.V2. It has an estimated 25% increase of transmissibility.POLYMORPHISM Variant Gamma/P.1 belongs to a lineage first isolated in Brazil (November 2020) and is also called 20J (V3) and GR/501Y.V3. It has an estimated 38% increase of transmissibility.POLYMORPHISM Variant Delta/B.1.617.2 belongs to a lineage first isolated in India (October 2020) and is also called G/478K.V1. It has an estimated 97% increase of transmissibility.POLYMORPHISM Variant Epsilon/B.1.427/B.1.429 belong to lineages first isolated in USA (Sept 2020). Variant S13I shifts the signal peptide cleavage site from S13-Q14 to C15-V16, thus removing Cys-15 which can no longer establish disulfide bonds with Cys-136. The latter would make a disulfid bond with Cys-152 (W152C variant), thereby changing the N-terminus structure of the protein and its antigenicity.POLYMORPHISM Variant Omicron/BA.1 belongs to a lineage first isolated in South Africa (November 2021).POLYMORPHISM Variant Omicron/BQ.1.1 belongs to a lineage first isolated in Nigeria (November 2022).POLYMORPHISM Variant Omicron/XBB.1.5 belongs to a lineage first isolated in United States (November 2022). It is the result of recombination between omicron BJ.1 and BM.1.1. Moreover XBB.1.5 do not express ORF8.BIOTECHNOLOGY Main component of the anti-COVID19 vaccines BNT162b2/Pfizer-Biontech and mRNA-1273/Moderna; in which the mutations of Lys-986 (K986P) and Val-987 (V987P) have been added to stabilize the protein in the prefusion state.BIOTECHNOLOGY Main component of the anti-COVID19 vaccine Ad26.COV2.S/Janssen Pharmaceutical; in which the mutations Arg-682 (R682S), Arg-685 (R685G), Lys-986 (K986P) and Val-987 (V987P) have been added to stabilize the protein in the prefusion state.BIOTECHNOLOGY Main component of the anti-COVID vaccine Chadox1/AZD1222/AstraZeneca; in which the human tPA leader sequence is added in N-terminus to enhance protein secretion.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).SIMILARITY Belongs to the betacoronaviruses spike protein family.CAUTION Asn-17, Asn-603, Asn-1134, Asn-1158, and Asn-1173 are not glycosylated when S1 or S2 are expressed individually in HEK293 cells.
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