Journal article
Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry
Cell reports (Cambridge), Vol.39(5), pp.110786-110786
05/03/2022
DOI: 10.1016/j.celrep.2022.110786
PMCID: PMC9015963
PMID: 35477024
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.
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•NTD-targeting antibodies block proteolytic activation of SARS-CoV-2 spike at S2•The NTD-to-S2′ signaling is conserved in SARS-CoV spike•An inter-monomer β sheet connects NTD ligation with proteolytic fusion activation•SARS-CoV-2 VOC NTDs enhance sensitivity for proteolytic fusion activation
Qing et al. identify connections between N-terminal and C-terminal domains of SARS-CoV-2 spike proteins that control the proteolytic activation of membrane fusion and show mechanisms of N-terminal domain-specific antibody neutralization.
Details
- Title: Subtitle
- Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry
- Creators
- Enya Qing - Loyola University ChicagoPengfei Li - University of IowaLaura Cooper - Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL 60607, USASebastian Schulz - Division of Molecular Immunology, Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, 91054 Erlangen, GermanyHans-Martin Jäck - Division of Molecular Immunology, Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, 91054 Erlangen, GermanyLijun Rong - Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL 60607, USAStanley Perlman - University of IowaTom Gallagher - Loyola University Chicago
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.39(5), pp.110786-110786
- DOI
- 10.1016/j.celrep.2022.110786
- PMID
- 35477024
- PMCID
- PMC9015963
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Language
- English
- Electronic publication date
- 04/19/2022
- Date published
- 05/03/2022
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9984252346502771
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