Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
Cell reports - 39(2022), 5 vom: 03. Mai, Seite 110786 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qing, Enya [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.05.2022 Date Revised 28.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2022.110786 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a coronavirus | |
| 650 | 4 | |a membrane fusion | |
| 650 | 4 | |a spike protein | |
| 650 | 4 | |a virus entry | |
| 650 | 4 | |a virus evolution | |
| 650 | 4 | |a virus neutralization | |
| 650 | 4 | |a virus variation | |
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| 700 | 1 | |a Li, Pengfei |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Schulz, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Jäck, Hans-Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Rong, Lijun |e verfasserin |4 aut | |
| 700 | 1 | |a Perlman, Stanley |e verfasserin |4 aut | |
| 700 | 1 | |a Gallagher, Tom |e verfasserin |4 aut | |
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