Cell Reports
Volume 39, Issue 5, 3 May 2022, 110786
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Article
Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry

https://doi.org/10.1016/j.celrep.2022.110786Get rights and content
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Highlights

  • NTD-targeting antibodies block proteolytic activation of SARS-CoV-2 spike at S2′

  • The NTD-to-S2′ signaling is conserved in SARS-CoV spike

  • An inter-monomer β sheet connects NTD ligation with proteolytic fusion activation

  • SARS-CoV-2 VOC NTDs enhance sensitivity for proteolytic fusion activation

Summary

SARS-CoV-2 continues to evolve into variants of concern (VOC), with greatest variability in the multidomain, entry-facilitating spike proteins. To recognize the significance of adaptive spike protein changes, we compare variant SARS-CoV-2 virus particles in several assays reflecting authentic virus-cell entry. Virus particles with adaptive changes in spike amino-terminal domains (NTDs) are hypersensitive to proteolytic activation of membrane fusion, an essential step in virus-cell entry. Proteolysis is within fusion domains (FDs), at sites over 10 nm from the VOC-specific NTD changes, indicating allosteric inter-domain control of fusion activation. In addition, NTD-specific antibodies block FD cleavage, membrane fusion, and virus-cell entry, suggesting restriction of inter-domain communication as a neutralization mechanism. Finally, using structure-guided mutagenesis, we identify an inter-monomer β sheet structure that facilitates NTD-to-FD transmissions and subsequent fusion activation. This NTD-to-FD axis that sensitizes viruses to infection and to NTD-specific antibody neutralization provides new context for understanding selective forces driving SARS-CoV-2 evolution.

Keywords

coronavirus
SARS-CoV-2
spike protein
virus entry
membrane fusion
virus neutralization
virus evolution
virus variation

Research topic(s)

CP: Microbiology

Data and code availability

  • All data reported in this paper will be shared by the lead contact upon request.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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