Abstract
SARS-CoV-2 spike protein plays a key role in mediating viral entry and inducing host immune responses. It can adopt either an open or closed conformation based on the position of its receptor-binding domain (RBD). It is yet unclear what cause these conformational changes or how they influence the spike's functions. Here we show that Lys417 in the RBD plays dual roles in the spike's structure: it stabilizes the closed conformation of the trimeric spike by mediating inter-spike-subunit interactions; it also directly interacts with ACE2 receptor. Hence, a K417V mutation has opposing effects on the spike's function: it opens up the spike for better ACE2 binding while weakening the RBD's direct binding to ACE2. The net outcomes of this mutation are to allow the spike to bind ACE2 with higher probability, mediate viral entry more efficiently, but become more exposed to neutralizing antibodies. Given that residue 417 has been a viral mutational hotspot, SARS-CoV-2 may have been evolving to strike a balance between infection potency and immune evasion, contributing to its pandemic spread.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source Data files have been provided for Figs 3 and 5. The atomic models and corresponding cryo-EM density maps have been deposited into the PDB and the Electron Microscopy Data Bank, respectively, with accession numbers PDB 8UUL and EMD-42589 (prototypic SARS-CoV-2 spike containing Lys417 in the closed conformation), PDB 8UUM and EMD-42590 (prototypic SARS-CoV-2 spike containing Lys417 in the open conformation), PDB 8UUN and EMD-42591 (prototypic SARS-CoV-2 spike containing Val417 in the closed conformation), and PDB 8UUO and EMD-42592 (prototypic SARS-CoV-2 spike containing Val417 in the open conformation).
Article and author information
Author details
Funding
National Institutes of Health (R01AI089728)
- Fang Li
National Institutes of Health (R01AI157975)
- Fang Li
National Institutes of Health (U19AI171954)
- Fang Li
National Institutes of Health (R01AI110700)
- Fang Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Geng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein
eLife 12:e74060.
https://doi.org/10.7554/eLife.74060
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