Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant [preprint]
Authors
Yurkovetskiy, LeonidNyalile, Thomas
Wang, Yetao
Diehl, William E.
Dauphin, Ann
Carbone, Claudia
Veinotte, Kristen
Egri, Shawn B.
Sabeti, Pardis C.
Kyratsous, Christos
Munro, James B
Shen, Kuang
Luban, Jeremy
UMass Chan Affiliations
Graduate School of Biomedical SciencesDepartment of Biochemistry and Molecular Pharmacology
Department of Microbiology and Physiological Systems
Program in Molecular Medicine
Document Type
PreprintPublication Date
2020-07-04Keywords
SARS-CoV-2COVID-19
microbiology
proteins
antibodies
virus genome sequence variants
D614G
Amino Acids, Peptides, and Proteins
Genetics and Genomics
Immunology and Infectious Disease
Infectious Disease
Microbiology
Nucleic Acids, Nucleotides, and Nucleosides
Virus Diseases
Metadata
Show full item recordAbstract
Virus genome sequence variants that appear over the course of an outbreak can be exploited to map the trajectory of the virus from one susceptible host to another. While such variants are usually of no functional significance, in some cases they may allow the virus to transmit faster, change disease severity, or confer resistance to antiviral therapies. Since the discovery of SARS-CoV-2 as the cause of COVID-19, the virus has spread around the globe, and thousands of SARS-CoV-2 genomes have been sequenced. The rate of sequence variation among SARS-CoV-2 isolates is modest for an RNA virus but the enormous number of human-to-human transmission events has provided abundant opportunity for selection of sequence variants. Among these, the SARS-CoV-2 Spike protein variant, D614G, was not present in the presumptive common ancestor of this zoonotic virus, but was first detected in late January in Germany and China. The D614G variant steadily increased in frequency and now constitutes >97% of isolates world-wide, raising the question whether D614G confers a replication advantage to SARS-CoV-2. Structural models predict that D614G would disrupt contacts between the S1 and S2 domains of the Spike protein and cause significant shifts in conformation. Using single-cycle vectors we showed that D614G is three to nine-fold more infectious than the ancestral form on human lung and colon cell lines, as well as on other human cell lines rendered permissive by ectopic expression of human ACE2 and TMPRSS2, or by ACE2 orthologues from pangolin, pig, dog, or cat. Nonetheless, monoclonal antibodies targeting the receptor binding domain of the SARS-CoV-2 Spike protein retain full neutralization potency. These results suggest that D614G was selected for increased human-to-human transmission, that it contributed to the rapidity of SARS-CoV-2 spread around the world, and that it does not confer resistance to antiviral therapies targeting the receptor binding domain.Source
bioRxiv 2020.07.04.187757; doi: 10.1101/2020.07.04.187757. Link to preprint on bioRxiv
DOI
10.1101/2020.07.04.187757Permanent Link to this Item
http://hdl.handle.net/20.500.14038/27621PubMed ID
32637944Notes
The PDF available for download is Version 1 of this preprint, which was posted with the title "SARS-CoV-2 Spike protein variant D614G increases infectivity and retains sensitivity to antibodies that target the receptor binding domain". The complete version history of this preprint is available at bioRxiv.
Related Resources
Now published in Cell, doi:https://doi.org/10.1016/j.cell.2020.09.032.
Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2020.07.04.187757
Scopus Count
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.