tetano
Editor, Senior Moderator
Cell Rep
. 2022 Apr 19;110786.
doi: 10.1016/j.celrep.2022.110786. Online ahead of print.
Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry
Enya Qing[SUP] 1 [/SUP], Pengfei Li[SUP] 2 [/SUP], Laura Cooper[SUP] 3 [/SUP], Sebastian Schulz[SUP] 4 [/SUP], Hans-Martin Jäck[SUP] 4 [/SUP], Lijun Rong[SUP] 3 [/SUP], Stanley Perlman[SUP] 2 [/SUP], Tom Gallagher[SUP] 5 [/SUP]
Affiliations
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.
. 2022 Apr 19;110786.
doi: 10.1016/j.celrep.2022.110786. Online ahead of print.
Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry
Enya Qing[SUP] 1 [/SUP], Pengfei Li[SUP] 2 [/SUP], Laura Cooper[SUP] 3 [/SUP], Sebastian Schulz[SUP] 4 [/SUP], Hans-Martin Jäck[SUP] 4 [/SUP], Lijun Rong[SUP] 3 [/SUP], Stanley Perlman[SUP] 2 [/SUP], Tom Gallagher[SUP] 5 [/SUP]
Affiliations
- PMID: 35477024
- DOI: 10.1016/j.celrep.2022.110786
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.