Adaptive changes in SARS-CoV-2 spike amino-terminal domains sensitize virus particles to proteolytic activation of membrane fusion via allosteric inter-domain control.
Identifies an allosteric inter-domain communication axis in SARS-CoV-2 spike proteins that controls fusion activation and is a target for neutralizing antibodies.
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.
Qing et al. (Tue,) conducted a other in SARS-CoV-2. Adaptive spike protein changes in amino-terminal domains (NTDs) was evaluated on Proteolytic activation of membrane fusion and virus-cell entry. Adaptive changes in SARS-CoV-2 spike amino-terminal domains sensitize virus particles to proteolytic activation of membrane fusion via allosteric inter-domain control.