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D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction.
<div class='caption-title'>SARS-CoV-2 Spike (S) Protein Ectodomain Platform for Characterizing the Structures, Antigenicity, and Protease Susceptibility of the S Protein and D614G Mutant</div>
<div class='caption-title'>Biophysics, Antigenicity, and Structure of the S-GSAS Ectodomain in Relation to S-GSAS/PP</div>
Gobeil SM, Janowska K, McDowell S, Mansouri K, Parks R, Manne K, Stalls V, Kopp MF, Henderson R, Edwards RJ, Haynes BF, Acharya P
OpenAccess logo Cell Rep 34 108630 (2021)
Related entries: 7kdg, 7kdi, 7kdj, 7kdk, 7kdl, 7ke4, 7ke6, 7ke7, 7ke8, 7ke9, 7kea, 7keb, 7kec

Cited: 192 times
EuropePMC logo PMID: 33417835

Abstract

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.

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