Abstract
SARS-CoV-2 continues to evolve into variants of concern (VOC), with greatest variability in the multidomain, entry-facilitating spike proteins. To recognize the significance of adaptive spike protein changes, we compare variant SARS-CoV-2 virus particles in several assays reflecting authentic virus-cell entry. Virus particles with adaptive changes in spike amino-terminal domains (NTDs) are hypersensitive to proteolytic activation of membrane fusion, an essential step in virus-cell entry. Proteolysis is within fusion domains (FDs), at sites over 10 nm from the VOC-specific NTD changes, indicating allosteric inter-domain control of fusion activation. In addition, NTD-specific antibodies block FD cleavage, membrane fusion, and virus-cell entry, suggesting restriction of inter-domain communication as a neutralization mechanism. Finally, using structure-guided mutagenesis, we identify an inter-monomer β sheet structure that facilitates NTD-to-FD transmissions and subsequent fusion activation. This NTD-to-FD axis that sensitizes viruses to infection and to NTD-specific antibody neutralization provides new context for understanding selective forces driving SARS-CoV-2 evolution.
Keywords: CP: Microbiology; SARS-CoV-2; coronavirus; membrane fusion; spike protein; virus entry; virus evolution; virus neutralization; virus variation.
【저자키워드】 SARS-CoV-2, coronavirus, Virus evolution, Spike protein, virus entry, Virus neutralization, membrane fusion, CP: Microbiology, virus variation., 【초록키워드】 Microbiology, adaptive, antibody, VoC, neutralization, Variation, Virus evolution, variant, Infection, variants of concern, SARS-CoV-2 virus, Transmission, virus, variants, Spike protein, Particle, virus entry, Virus neutralization, membrane, cleavage, SARS-CoV-2 evolution, proteolysis, membrane fusion, NTD, mechanism, Antibody neutralization, Mutagenesis, Spike proteins, changes, restriction, domain, Variability, virus particles, NTDs, selective, proteolytic activation, driving, fusion activation, identify, virus, subsequent, addition, facilitate, provide, changes in, recognize, hypersensitive, SARS-CoV-2 virus particle, 【제목키워드】 SARS-CoV-2 spike protein, Control, cell entry, Inter-domain,