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D614G mutation alters SARS-CoV-2 spike conformation and enhances protease cleavage at the S1/S2 junction
- Source :
- Cell Reports, Cell Reports, Vol 34, Iss 2, Pp 108630-(2021)
- Publication Year :
- 2020
- Publisher :
- The Author(s)., 2020.
-
Abstract
- The SARS-CoV-2 spike (S) protein is the target of vaccine design efforts to end the 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 spike conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryo-EM structures reveal altered 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 Receptor Binding Domains (RBD) in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, that harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 spike conformational landscape and allostery, and have implications for vaccine design.<br />Graphical Abstract<br />Highlights • SARS-CoV-2 S 2P mutations do not impact its structure, stability or antigenicity. • D614G mutation increases RBD “up” state and enhances S1/S2 junction proteolysis. • Structure and antigenicity reveal allostery between the S1/S2 junction and RBD. • SD2 anchors the mobile RBD and NTD, separating large S1 subunit motions from S2.<br />SARS-CoV-2 spike undergoes large conformational changes during cell fusion. Gobeil et al. identify a subdomain anchor that limits large motions in the receptor binding subunit of the pre-fusion spike from propagating to its fusion subunit. They demonstrate that the D614G mutation increases rate of furin cleavage, which may impact infectivity.
- Subjects :
- 0301 basic medicine
Mutation rate
medicine.medical_treatment
viruses
Protein domain
Allosteric regulation
Molecular Dynamics Simulation
medicine.disease_cause
Cleavage (embryo)
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
0302 clinical medicine
Immunogenicity, Vaccine
Protein Domains
medicine
Humans
Protein Structure, Quaternary
skin and connective tissue diseases
lcsh:QH301-705.5
Furin
Coronavirus
2P
allostery
Protease
biology
Chemistry
Protein Stability
SARS-CoV-2
Cryoelectron Microscopy
COVID-19
spike
D614G
Cell biology
Protein Subunits
030104 developmental biology
lcsh:Biology (General)
Ectodomain
Mutation
Proteolysis
Spike Glycoprotein, Coronavirus
biology.protein
030217 neurology & neurosurgery
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....0e3ef0190f8cf8018afcd5c70f8d501b