Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein

Abstract
Data availability
Article and author information
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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).

The following data sets were generated

1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Lys417 in the closed conformation
PDB, 8UUL.

https://www.rcsb.org/structure/8UUL
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Lys417 in the closed conformation
EMDB, EMD-42589.

https://www.ebi.ac.uk/emdb/EMD-42589
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Lys417 in the open conformation
PDB, 8UUM.

https://www.rcsb.org/structure/8UUM
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Lys417 in the open conformation
EMDB, EMD-42590.

https://www.ebi.ac.uk/emdb/EMD-42590
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Val417 in the closed conformation
PDB, 8UUN.

https://www.rcsb.org/structure/8UUN
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Val417 in the closed conformation
EMDB, EMD-42591.

https://www.ebi.ac.uk/emdb/EMD-42591
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Val417 in the open conformation
PDB, 8UUO.

https://www.rcsb.org/structure/8UUO
1. Li F
2. et al
(2023) prototypic SARS-CoV-2 spike containing Val417 in the open conformation
EMDB, EMD-42592.

https://www.ebi.ac.uk/emdb/EMD-42592

Article and author information

Author details

Qibin Geng

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Yushun Wan

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Fu-Chun Hsueh

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Jian Shang

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Gang Ye

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6034-2174
Fan Bu

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Morgan Herbst

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Rowan Wilkens

Department of Pharmacology, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Bin Liu

Hormel Institute, University of Minnesota, Austin, United States

For correspondence
liu00794@umn.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6581-780X
Fang Li

Department of Pharmacology, University of Minnesota, Minneapolis, United States

For correspondence
lifang@umn.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1958-366X

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

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.