The F1148 hydrophobic lock: A critical determinant of SARS-CoV-2 spike protein-mediated membrane fusion via the 3H/CH cavity.

ABSTRACT: The S2 subunit of the coronavirus Spike protein undergoes extensive conformational refolding to drive membrane fusion during viral entry. Although the HR1/HR2 six-helix bundle (6-HB) is recognized as the core mediator of fusion, the molecular driving force governing its formation remains poorly elucidated. Here, through systematic mutagenesis of the AlphaFold-predicted stem helix (SH) region in S2, followed by analysis of the resulting SC2-VLP entry phenotypes, we identified key amino acid residues within conserved helices that are present in both prefusion and postfusion Spike conformations. These elements, which we term postfusion-preserved helices (PFPHs), were found to be critical for SC2-VLP entry. Structural analysis revealed a "hydrolock" interaction between F1148 in PFPH-1 and a co

SUBMITTER: Lei F 

PROVIDER: S-EPMC12459827 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature