8gb0 | pdb_00008gb0
SARS-CoV-2 Spike H655Y variant, One RBD Open
Structural highlights
FunctionSPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). 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:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099][1] [2] [3] 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.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Publication Abstract from PubMedSARS-CoV-2 variants bearing complex combinations of mutations have been associated with increased transmissibility, COVID-19 severity, and immune escape. S:D614G may have facilitated emergence of such variants since they appeared after S:D614G had gone to fixation. To test this hypothesis, Spike sequences from an immunocompromised individual with prolonged infection, and from the major SARS-CoV-2 variants of concern, were reverted to the ancestral S:D614. In all cases, infectivity of the revertants was compromised. Rare SARS-CoV-2 lineages that lack S:D614G were identified and the infectivity of these was dependent upon S:Q613H or S:H655Y. Notably, Gamma and Omicron variants possess both S:D614G and S:H655Y, each of which contributed to infectivity of these variants. All three mutations, S:Q613H, S:D614G, and S:H655Y, stabilized Spike on virions, consistent with selection of these mutations by a common molecular mechanism. Among sarbecoviruses, S:Q613H, S:D614G, and S:H655Y are only detected in SARS-CoV-2, which uniquely possesses a polybasic S1/S2 cleavage site. Results of genetic and biochemical experiments here demonstrated that S:D614G and S:H655Y are likely adaptations to the cleavage site. CryoEM revealed that both mutations shift the Spike receptor binding domain towards the open conformation required for ACE2-binding and Spikes bearing either S:D614G or S:H655Y spontaneously mimic the smFRET signal that ACE2 induces in the parental molecule. Data from these orthogonal experiments demonstrate that S:D614G and S:H655Y are convergent adaptations to the polybasic S1/S2 cleavage site, which stabilize S1 on the virion in the open RBD conformation that is on-pathway for target cell fusion, and thereby act epistatically to promote the fitness of variants bearing complex combinations of clinically significant mutations. HIGHLIGHTS: S:D614G is ubiquitous among SARS-CoV-2 B-lineage Spikes and is required for infectivity of the main Variants of ConcernIn an example of convergent evolution, rare SARS-CoV-2 A lineage viruses maintained transmission chains in the absence of S:D614G, but were instead dependent upon S:Q613H or S:H655YS:D614G and S:H655Y are both adaptations to the polybasic S1/S2 cleavage siteIncreased infectivity of S:D614G and S:H655Y is associated with a more open RBD conformation and increased steady-state levels of virion-associated S1. S:D614G and S:H655Y are gateway mutations that act epistatically to promote SARS-CoV-2 variant fitness.,Yurkovetskiy L, Egri S, Kurhade C, Diaz-Salinas MA, Jaimes JA, Nyalile T, Xie X, Choudhary MC, Dauphin A, Li JZ, Munro JB, Shi PY, Shen K, Luban J bioRxiv. 2023 Mar 31:2023.03.30.535005. doi: 10.1101/2023.03.30.535005. Preprint. PMID:37034621[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||
