Probing SARS-CoV-2 membrane binding peptide via single-molecule AFM-based force spectroscopy.

Nat Commun

Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain, Croix du sud 4-5, L7.07.07, Louvain-la-Neuve, Belgium.

Published: January 2025

The SARS-CoV-2 spike protein's membrane-binding domain bridges the viral and host cell membrane, a critical step in triggering membrane fusion. Here, we investigate how the SARS-CoV-2 spike protein interacts with host cell membranes, focusing on a membrane-binding peptide (MBP) located near the TMPRSS2 cleavage site. Through in vitro and computational studies, we examine both primed (TMPRSS2-cleaved) and unprimed versions of the MBP, as well as the influence of its conserved disulfide bridge on membrane binding. Our results show that the MBP preferentially associates with cholesterol-rich membranes, and we find that cholesterol depletion significantly reduces viral infectivity. Furthermore, we observe that the disulfide bridge stabilizes the MBP's interaction with the membrane, suggesting a structural role in viral entry. Together, these findings highlight the importance of membrane composition and peptide structure in SARS-CoV-2 infectivity and suggest that targeting the disulfide bridge could provide a therapeutic strategy against infection.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696146PMC
http://dx.doi.org/10.1038/s41467-024-55358-9DOI Listing

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