Effect of the S2’ site cleavage on SARS-CoV-2 spike

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2' site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2' cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2' cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

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Publication Details

Journal
Nature Communications
Published
2025-11-27
DOI
https://doi.org/10.1038/s41467-025-66693-w
Citations
1
Primary Topic
Lipid Membrane Structure and Behavior
Type
article
Field-Weighted Citation Impact
0.81

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article

Effect of the S2’ site cleavage on SARS-CoV-2 spike

Richard M. Walsh, Jacob N. Allen, Hanqin Peng, Sophia Rits‐Volloch et al.
1 citations
Nature Communications
Lipid Membrane Structure and Behavior
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article

Effect of the S2’ site cleavage on SARS-CoV-2 spike

Richard M. Walsh, Jacob N. Allen, Hanqin Peng, Sophia Rits‐Volloch, Haisun Zhu, G. M. Jonaid, Md. Golam Kibria, Bing Chen, Shaowei Wang, Wei Shi, Jianming Lu
article en
1 citations

Abstract

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2' site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2' cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2' cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

Nature CommunicationsVol. 16(1)
Boston Children's Hospital (US), Harvard University (US), Georgetown University (US), Wuhan University (CN), RegeneRx Biopharmaceuticals (United States) (US), Institute for Protein Innovation (US), Renmin Hospital of Wuhan University (CN)
Massachusetts Consortium on Pathogen Readiness, National Institutes of Health
Openalex Percentile: Top 21%
Lipid Membrane Structure and Behavior
0.81
DOIOpen Access PDFOpenAlex
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