tetano
Editor, Senior Moderator
Cell Rep
. 2020 Dec 26;108630.
doi: 10.1016/j.celrep.2020.108630. Online ahead of print.
D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction
Sophie M-C Gobeil[SUP] 1 [/SUP], Katarzyna Janowska[SUP] 1 [/SUP], Shana McDowell[SUP] 1 [/SUP], Katayoun Mansouri[SUP] 1 [/SUP], Robert Parks[SUP] 1 [/SUP], Kartik Manne[SUP] 1 [/SUP], Victoria Stalls[SUP] 1 [/SUP], Megan F Kopp[SUP] 1 [/SUP], Rory Henderson[SUP] 2 [/SUP], Robert J Edwards[SUP] 2 [/SUP], Barton F Haynes[SUP] 3 [/SUP], Priyamvada Acharya[SUP] 4 [/SUP]
Affiliations
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.
Keywords: 2P; COVID-19; D614G; SARS-CoV-2; allostery; cryo-EM; furin cleavage; spike.
. 2020 Dec 26;108630.
doi: 10.1016/j.celrep.2020.108630. Online ahead of print.
D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction
Sophie M-C Gobeil[SUP] 1 [/SUP], Katarzyna Janowska[SUP] 1 [/SUP], Shana McDowell[SUP] 1 [/SUP], Katayoun Mansouri[SUP] 1 [/SUP], Robert Parks[SUP] 1 [/SUP], Kartik Manne[SUP] 1 [/SUP], Victoria Stalls[SUP] 1 [/SUP], Megan F Kopp[SUP] 1 [/SUP], Rory Henderson[SUP] 2 [/SUP], Robert J Edwards[SUP] 2 [/SUP], Barton F Haynes[SUP] 3 [/SUP], Priyamvada Acharya[SUP] 4 [/SUP]
Affiliations
- PMID: 33417835
- PMCID: PMC7762703
- DOI: 10.1016/j.celrep.2020.108630
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.
Keywords: 2P; COVID-19; D614G; SARS-CoV-2; allostery; cryo-EM; furin cleavage; spike.