Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants

Zunlong Ke; Thomas P Peacock; Jonathan C Brown; Carol M Sheppard; Tristan I Croll; Abhay Kotecha; Daniel H Goldhill; Wendy S Barclay; John A G Briggs

doi:10.1038/s44318-024-00303-1

Virion morphology and on-virus spike protein structures of diverse SARS-CoV-2 variants

EMBO J. 2024 Nov 14. doi: 10.1038/s44318-024-00303-1. Online ahead of print.

Authors

Zunlong Ke^{1

2

3}, Thomas P Peacock^{4

5}, Jonathan C Brown⁴, Carol M Sheppard⁴, Tristan I Croll^{6

7}, Abhay Kotecha⁸, Daniel H Goldhill^{4

9}, Wendy S Barclay⁴, John A G Briggs^{10

11}

Affiliations

¹ Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany.
² Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
³ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
⁴ Department of Infectious Disease, Imperial College London, London, UK.
⁵ The Pirbright Institute, Woking, UK.
⁶ Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
⁷ Altos Labs, Cambridge, UK.
⁸ Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, The Netherlands.
⁹ Department of Pathobiology and Population Sciences, Royal Veterinary College, London, UK.
¹⁰ Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany. [email protected].
¹¹ Structural Studies Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. [email protected].

PMID: 39543395
DOI: 10.1038/s44318-024-00303-1

Abstract

The evolution of SARS-CoV-2 variants with increased fitness has been accompanied by structural changes in the spike (S) proteins, which are the major target for the adaptive immune response. Single-particle cryo-EM analysis of soluble S protein from SARS-CoV-2 variants has revealed this structural adaptation at high resolution. The analysis of S trimers in situ on intact virions has the potential to provide more functionally relevant insights into S structure and virion morphology. Here, we characterized B.1, Alpha, Beta, Gamma, Delta, Kappa, and Mu variants by cryo-electron microscopy and tomography, assessing S cleavage, virion morphology, S incorporation, "in-situ" high-resolution S structures, and the range of S conformational states. We found no evidence for adaptive changes in virion morphology, but describe multiple different positions in the S protein where amino acid changes alter local protein structure. Taken together, our data are consistent with a model where amino acid changes at multiple positions from the top to the base of the spike cause structural changes that can modulate the conformational dynamics of the S protein.

Keywords: Coronavirus; Cryo-electron Tomography; Membrane Fusion Protein; Virus Evolution; Virus Structure.

Abstract

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