D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction.

Cell Reports
Sophie GobeilPriyamvada Acharya

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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Citations

Feb 27, 2021·Briefings in Bioinformatics·Jim Warwicker
Mar 17, 2021·Wiener klinische Wochenschrift·Franz X Heinz, Karin Stiasny
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Datasets Mentioned

BETA
MN908947

Methods Mentioned

BETA
size-exclusion chromatography
electron microscopy
ELISA
differential
Transfection

Software Mentioned

RELION
ImageJ
GraphPad
R R
Bio3D
PRISM

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