Cell entry mechanisms of SARS-CoV-2
Top Cited Papers
Open Access
- 6 May 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (21), 11727-11734
- https://doi.org/10.1073/pnas.2003138117
Abstract
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.Keywords
Funding Information
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI089728)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI110700)
This publication has 50 references indexed in Scilit:
- Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike ProteinViruses, 2012
- Ready, Set, Fuse! The Coronavirus Spike Protein and Acquisition of Fusion CompetenceViruses, 2012
- SARS-CoV and emergent coronaviruses: viral determinants of interspecies transmissionCurrent Opinion in Virology, 2011
- Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategyProceedings of the National Academy of Sciences of the United States of America, 2011
- Coronaviruses post-SARS: update on replication and pathogenesisNature Reviews Microbiology, 2009
- The spike protein of SARS-CoV — a target for vaccine and therapeutic developmentNature Reviews Microbiology, 2009
- Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27–restricted human immune responseJCI Insight, 2009
- Mechanisms of Severe Acute Respiratory Syndrome Pathogenesis and Innate ImmunomodulationMicrobiology and Molecular Biology Reviews, 2008
- Conformational States of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein EctodomainJournal of Virology, 2006
- HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sitesNature, 2002