D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction.
The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form ... worldwide. Here, we explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design.
Mesh Terms:
COVID-19, Cryoelectron Microscopy, Humans, Immunogenicity, Vaccine, Molecular Dynamics Simulation, Mutation, Peptide Hydrolases, Protein Domains, Protein Stability, Protein Structure, Quaternary, Protein Subunits, Proteolysis, SARS-CoV-2, Spike Glycoprotein, Coronavirus
COVID-19, Cryoelectron Microscopy, Humans, Immunogenicity, Vaccine, Molecular Dynamics Simulation, Mutation, Peptide Hydrolases, Protein Domains, Protein Stability, Protein Structure, Quaternary, Protein Subunits, Proteolysis, SARS-CoV-2, Spike Glycoprotein, Coronavirus
Cell Rep
Date: Dec. 12, 2020
PubMed ID: 33417835
View in: Pubmed Google Scholar
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