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Nature communications2025; 17(1); 435; doi: 10.1038/s41467-025-66330-6

Structural insights into VLDLR recognition by western equine encephalitis virus.

Abstract: Western equine encephalitis virus (WEEV), a group of encephalitic alphaviruses that cause severe diseases in humans and equids, historically used the very-low-density lipoprotein receptor (VLDLR) as a receptor during infection. However, current epidemic strains no longer use VLDLR as a receptor. In this study, we identify that LA1, LA2, LA3, and LA5 of VLDLR can directly interact with WEEV. Using cryo-electron microscopy, we investigate the structures of complexes formed between WEEV and VLDLR-LBD or other VLDLR fragments. Our findings show that LA1 and LA2 insert into a cleft formed by two adjacent E2-E1 heterodimers within a single trimeric spike, while LA3 and LA5 interact with the DIII region of WEEV E1. Among VLDLR concatemers, the LA1-5 exhibits the strongest binding affinity for WEEV. Additionally, we find that a single polymorphism in the E2 glycoprotein determines WEEV's receptor tropism. Mutations E181K or E81K in the nonpathogenic strain Imperial-181 enhanced its ability to enter via VLDLR. These results enhance our understanding of alphavirus receptor recognition and receptor usage shifts, providing insights for the development of antiviral therapies.
© 2025. The Author(s).
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Publication Date: 2025-12-06 PubMed ID: 41353198PubMed Central: PMC12800238DOI: 10.1038/s41467-025-66330-6Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates how the Western equine encephalitis virus (WEEV) recognizes and binds the very-low-density lipoprotein receptor (VLDLR) to infect host cells.
  • It identifies specific regions of the VLDLR that interact with WEEV and explains how a mutation in the virus affects its ability to use VLDLR for infection, providing insights helpful for antiviral development.

Background

  • Western equine encephalitis virus (WEEV) is an alphavirus that causes severe neurological diseases in humans and horses.
  • WEEV historically uses the very-low-density lipoprotein receptor (VLDLR) to enter host cells, but current epidemic strains have lost this ability.
  • Understanding the molecular basis of virus-receptor interaction is critical for designing antiviral therapies and understanding virus evolution.

Objectives

  • Identify the specific domains within the VLDLR protein that interact directly with WEEV.
  • Determine the structural basis of WEEV binding using cryo-electron microscopy.
  • Examine how mutations in the WEEV envelope protein influence receptor usage and host cell entry.

Key Methods

  • Protein interaction assays identified which ligand-binding repeats (LAs) of VLDLR engage with WEEV.
  • Cryo-electron microscopy was employed to visualize the complex of WEEV and different fragments of VLDLR at molecular resolution.
  • Mutagenesis was used to create specific point mutations in the viral E2 glycoprotein to study effects on receptor interaction and viral entry.

Main Findings

  • VLDLR repeats LA1, LA2, LA3, and LA5 directly bind to WEEV.
  • LA1 and LA2 inserts into a cleft formed by two adjacent E2-E1 heterodimers in a single trimeric spike structure on the virus surface.
  • LA3 and LA5 engage with the DIII domain of WEEV E1 glycoprotein.
  • The concatemer of LA1-5 repeats showed the strongest binding affinity to WEEV, suggesting cooperativity between domains enhances receptor recognition.
  • A single amino acid polymorphism in the viral E2 glycoprotein (mutations E181K or E81K) increased binding to and entry via VLDLR in a nonpathogenic WEEV strain (Imperial-181).
  • This implies that receptor tropism and usage can shift due to small genetic changes in the virus.

Significance and Implications

  • Structural insights clarify exactly how WEEV engages VLDLR on host cells, highlighting key contact points and binding mechanisms.
  • Understanding the precise binding interactions provides a molecular basis for why current epidemic strains may have altered receptor usage.
  • The discovery of how a single viral mutation can restore or enhance VLDLR usage underscores the potential for rapid evolutionary adaptations impacting viral tropism and pathogenesis.
  • This knowledge is valuable for designing antiviral therapies that block viral entry by targeting these key interaction sites.
  • It also aids in predicting how alphaviruses might change in the future to infect new hosts or evade immune responses.

Cite This Article

APA
Liang S, Xu Z, Liu X, Yang Y, Zhao L, Hu C, Hou J, Wei Z, Zhang Y, Li D, Yang J, Zhang J, Bi J, Wang Y, Lou Z. (2025). Structural insights into VLDLR recognition by western equine encephalitis virus. Nat Commun, 17(1), 435. https://doi.org/10.1038/s41467-025-66330-6

Publication

Nature communications
ISSN: 2041-1723
NlmUniqueID: 101528555
Country: England
Language: English
Volume: 17
Issue: 1
Pages: 435
PII: 435

Researcher Affiliations

Liang, Shengjian
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China. liangsj22@mails.tsinghua.edu.cn.
Xu, Zhili
  • Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Liu, Xiaoke
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Yang, Yan
  • Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
Zhao, Lixin
  • Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • University of Chinese Academy of Sciences, Beijing, China.
Hu, Chuyu
  • Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
Hou, Jichao
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Wei, Zhenyu
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Zhang, Yan
  • School of Public Health, Beihua University, Jilin, China.
Li, Donghan
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Yang, Jinwei
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Zhang, Jiayi
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Bi, Jundong
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Wang, Yanyi
  • Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China. wangyy@wh.iov.cn.
Lou, Zhiyong
  • School of Basic Medical Sciences, Tsinghua University, Beijing, China. louzy@mail.tsinghua.edu.cn.

MeSH Terms

  • Receptors, LDL / metabolism
  • Receptors, LDL / chemistry
  • Receptors, LDL / genetics
  • Receptors, LDL / ultrastructure
  • Cryoelectron Microscopy
  • Animals
  • Humans
  • Encephalitis Virus, Western Equine / metabolism
  • Encephalitis Virus, Western Equine / genetics
  • Protein Binding
  • Receptors, Virus / metabolism
  • Receptors, Virus / chemistry
  • Receptors, Virus / genetics
  • Mutation
  • Viral Envelope Proteins / metabolism
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / chemistry
  • Models, Molecular
  • Horses
  • HEK293 Cells
  • Encephalomyelitis, Equine / virology

Conflict of Interest Statement

Competing interests: The authors declare no competing interests.

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