Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
Program in Molecular Medicine; Department of Microbiology and Physiological Systems; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
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
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.
ACE2, COVID-19, SARS-CoV-2, Spike protein, coronavirus, cryo-electron microscopy, infectivity, neutralizing antibody, pandemic
DOI of Published Version
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
Yurkovetskiy L, Nyalile T, Wang Y, Diehl WE, Dauphin A, Carbone C, Veinotte K, Egri S, Munro JB, Sabeti PC, Kyratsous CA, Dudkina NV, Shen K, Luban J. (2020). Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. COVID-19 Publications by UMMS Authors. https://doi.org/10.1016/j.cell.2020.09.032. Retrieved from https://escholarship.umassmed.edu/covid19/126