Title

Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant

UMMS Affiliation

Program in Molecular Medicine; Department of Microbiology and Physiological Systems; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences

Publication Date

2020-10-29

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Genetics and Genomics | Immunology and Infectious Disease | Infectious Disease | Microbiology | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Structural Biology | Virus Diseases

Abstract

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.

Keywords

ACE2, COVID-19, SARS-CoV-2, Spike protein, coronavirus, cryo-electron microscopy, infectivity, neutralizing antibody, pandemic

DOI of Published Version

10.1016/j.cell.2020.09.032

Source

Yurkovetskiy L, Wang X, Pascal KE, Tomkins-Tinch C, Nyalile TP, Wang Y, Baum A, Diehl WE, Dauphin A, Carbone C, Veinotte K, Egri SB, Schaffner SF, Lemieux JE, Munro JB, Rafique A, Barve A, Sabeti PC, Kyratsous CA, Dudkina NV, Shen K, Luban J. Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell. 2020 Oct 29;183(3):739-751.e8. doi: 10.1016/j.cell.2020.09.032. Epub 2020 Sep 15. PMID: 32991842; PMCID: PMC7492024. Link to article on publisher's site

Journal/Book/Conference Title

Cell

Comments

This article is based on a previously available preprint on bioRxiv that is also available in eScholarship@UMMS.

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

32991842

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