Structural and functional basis of VLDLR usage by Eastern equine encephalitis virus.
Cell
; 187(2): 360-374.e19, 2024 01 18.
Article
em En
| MEDLINE
| ID: mdl-38176410
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de LDL
/
Microscopia Crioeletrônica
/
Vírus da Encefalite Equina do Leste
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Encefalomielite Equina
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article