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Insights into the mechanism of action of the bipartite fusion module of SARS-CoV-2 spike protein

2026-09-15Artigo de investigação Acesso aberto
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dc.contributor.authorBuga, Carolina C.
dc.contributor.authorValerio, Mariana
dc.contributor.authorAlenquer, Marta
dc.contributor.authorMiranda, Marta Pires de
dc.contributor.authorMelo, Manuel N.
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorAmorim, Maria João
dc.contributor.authorSoares, Cláudio M.
dc.contributor.authorVicente, João B.
dc.contributor.authorVeiga, Ana Salomé
dc.contributor.authorLousa, Diana
dc.date.accessioned2026-09-24T16:01:54Z
dc.date.available2026-09-24T16:01:54Z
dc.date.issued2026-09-15
dc.description.abstractSARS-CoV-2 entry into host cells is mediated by the spike glycoprotein, which promotes fusion between viral and host membranes. Despite its importance, the precise location and mode of action of the fusion peptide, a key spike region that inserts into and perturbs the host membrane, remain elusive. Two regions have been proposed as fusion peptides: one located at the N-terminus of the protein (nFP) and the other at an internal position (iFP). Here, we combine computational and experimental approaches to characterize their roles and impact on membrane fusion. Molecular dynamics (MD) simulations indicated that the nFP interacts mostly at the membrane surface. Consistently, experimental biophysical assays revealed that the nFP exhibits low affinity and weak perturbing effects on lipid vesicles. In contrast, the iFP exhibits stronger membrane binding and induces stronger perturbation in vitro. MD simulations show that the iFP inserts deeply into and strongly affects the membrane, inducing lipid tail protrusion and increased water flux through the bilayer. Moreover, spike-pseudotyped lentiviruses carrying mutations in the iFP region showed that residues Y873, F888, and F906 are required for viral entry. Together, our findings suggest that SARS-CoV-2 uses a bipartite fusion module in which the nFP establishes initial contact with the host membrane and primes the bilayer, enabling subsequent deep insertion and further membrane destabilization promoted by the iFP. Given that FPs are conserved across viral families, a similar fusion module may be present in other coronaviruses, making this region a promising target for the development of broad-range antiviral therapeutics.eng
dc.identifier.doi10.1128/jvi.00688-26
dc.identifier.other5942beb7-9a86-4781-b2b8-13f14f051647
dc.identifier.pmid42742222
dc.identifier.urihttp://hdl.handle.net/10400.14/59575
dc.identifier.wos001875277100001
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Society for Microbiology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectSARS-CoV-2eng
dc.subjectExperimental and computational biophysicseng
dc.subjectFusion peptideeng
dc.subjectMembrane fusioneng
dc.subjectViral entryeng
dc.titleInsights into the mechanism of action of the bipartite fusion module of SARS-CoV-2 spike protein
dc.typeresearch article
dspace.entity.typePublication
oaire.versionhttp://purl.org/coar/version/c_ab4af688f83e57aa

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