Progressive membrane-binding mechanism of SARS-CoV-2 variant spike proteins

• Published in: iScience Vol. 25; no. 8; p. 104722
• Main Authors: Overduin, Michael, Kervin, Troy A., Tran, Anh
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 19-08-2022; Elsevier
• Subjects: Protein structure aspects; Structural biology; Virology; Structural biology; Protein structure aspects; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.104722

Membrane recognition by viral spike proteins is critical for infection. Here we show the host cell membrane-binding surfaces of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike variants Alpha, Beta, Gamma, Delta, Epsilon, Kappa, and Omicron as well as SARS-CoV-1 and pangolin and bat relatives. They show increases in membrane binding propensities over time, with all spike head mutations in variants, and particularly BA.1, impacting the protein’s affinity to cell membranes. Comparison of hundreds of structures yields a progressive model of membrane docking in which spike protein trimers shift from initial perpendicular stances to increasingly tilted positions that draw viral particles alongside host cell membranes before optionally engaging angiotensin-converting enzyme 2 (ACE2) receptors. This culminates in the assembly of the symmetric fusion apparatus, with enhanced membrane interactions of variants explaining their unique cell fusion capacities and COVID-19 disease transmission rates.
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•Betacoronaviruses including SARS-CoV-2 bind membranes via spike protein heads•Membrane-binding propensities are enhanced in variants, particularly in Omicron BA.1•Networks of perpendicular and tilted states of spikes facilitate host cell docking•Cell entry can occur through ACE2-dependent and independent routes
Virology; Structural biology; Protein structure aspects