Structural and functional basis of VLDLR usage by Eastern equine encephalitis virus
Copyright © 2023 Elsevier Inc. All rights reserved..
The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:187 |
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| Enthalten in: |
Cell - 187(2024), 2 vom: 18. Jan., Seite 360-374.e19 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Adams, Lucas J [VerfasserIn] |
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| Links: |
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| Themen: |
Alphavirus |
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| Anmerkungen: |
Date Completed 29.01.2024 Date Revised 12.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Nov 15;:. - PMID 38014196 Citation Status MEDLINE |
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| doi: |
10.1016/j.cell.2023.11.031 |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Diamond, Michael S |e verfasserin |4 aut | |
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