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Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry.
Qing, Enya; Li, Pengfei; Cooper, Laura; Schulz, Sebastian; Jäck, Hans-Martin; Rong, Lijun; Perlman, Stanley; Gallagher, Tom.
  • Qing E; Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA.
  • Li P; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA.
  • Cooper L; Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL 60607, USA.
  • Schulz S; Division of Molecular Immunology, Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, 91054 Erlangen, Germany.
  • Jäck HM; Division of Molecular Immunology, Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, 91054 Erlangen, Germany.
  • Rong L; Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL 60607, USA.
  • Perlman S; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA.
  • Gallagher T; Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: tgallag@luc.edu.
Cell Rep ; 39(5): 110786, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1797092
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 ß 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Cell Rep Year: 2022 Document Type: Article Affiliation country: J.celrep.2022.110786

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Cell Rep Year: 2022 Document Type: Article Affiliation country: J.celrep.2022.110786