The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes

Eastern Equine Encephalitis virus (EEEV) is an alphavirus that can cause severe diseases in infected humans. The very low-density lipoprotein receptor (VLDLR) was recently identified as a receptor of EEEV. Herein, we performed cryo-electron microscopy structural and biochemistry studies on the speci...

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Vydáno v:Nature communications Ročník 15; číslo 1; s. 6866 - 15
Hlavní autoři: Cao, Duanfang, Ma, Bingting, Cao, Ziyi, Xu, Xiaoyu, Zhang, Xinzheng, Xiang, Ye
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 10.08.2024
Nature Publishing Group
Nature Portfolio
Témata:
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631/326/596/1282
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Animals
Binding
Binding Sites
Cell adhesion
Cryoelectron Microscopy
Density
Eastern equine encephalitis
Electron microscopy
Encephalitis
Encephalitis Virus, Eastern Equine - genetics
Encephalitis Virus, Eastern Equine - metabolism
Gene sequencing
HEK293 Cells
Humanities and Social Sciences
Humans
Low density lipoprotein receptors
Models, Molecular
multidisciplinary
Mutation
Protein Binding
Receptor density
Receptors
Receptors, LDL - genetics
Receptors, LDL - metabolism
Receptors, Virus - metabolism
Science
Science (multidisciplinary)
Single-nucleotide polymorphism
Virus Attachment
Viruses
ISSN:2041-1723, 2041-1723
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Popis
Shrnutí:Eastern Equine Encephalitis virus (EEEV) is an alphavirus that can cause severe diseases in infected humans. The very low-density lipoprotein receptor (VLDLR) was recently identified as a receptor of EEEV. Herein, we performed cryo-electron microscopy structural and biochemistry studies on the specific interactions between EEEV and VLDLR. Our results show that VLDLR binds EEEV at three different sites A, B and C through its membrane-distal LDLR class A (LA) repeats. Site A is located in the cleft in between the E1-E2 heterodimers. Site B is located near the connecting β ribbon of E2 and is in proximity to site A, while site C is on the domain B of E2. The binding of VLDLR LAs to EEEV is in complex modes, including the LA1-2 and LA3-5 mediated two major modes. Disruption of the LA1-2 mediated binding significantly affect the cell attachment of EEEV. However, the mutation W132G of VLDLR impairs the binding of LA3, drives the switch of the binding modes, and significantly enhances the attachment of EEEV to the cell. The W132G variant of VLDLR could be identified in human genome and SNP sequences, implying that people with similar mutations in VLDLR may be highly susceptible to EEEV infection. Eastern equine encephalitis virus (EEEV) uses the very low-density lipoprotein receptor (VLDLR) to infect cells of different species. This study finds that the ecto LA repeats of VLDLR binds EEEV at three distinct sites, generating multiple different binding modes that facilitate the cross-species transmission of EEEV.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-51293-x