SARS-CoV-2 Spike S1+S2 (mut L18F+T20N+P26S+D138Y+R190S+K417T+E484K+N501Y+D614G+H655Y+T1027I+V1176F)

일반 정보

기능

Spike protein S1. 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).. Spike protein S2. 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.. Spike protein S2'. 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.

서열 유사성

Belongs to the betacoronaviruses spike protein family.

Post-translational modifications

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.. 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).. 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).. O-glycosylated by host GALNT1 at the end of S1. This could reduce the efficiency of S1/S2 cleavage.