Structural insights into VLDLR recognition by western equine encephalitis virus.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41353198.
- Also identified by DOI 10.1038/s41467-025-66330-6 and PMC identifier 12800238.
- Licence recorded as CC BY-NC-ND.
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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 <sub>E2</sub>E181K or <sub>E2</sub>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.
Medical subject headings
- Receptors, LDL
- Encephalitis Virus, Western Equine
- Receptors, Virus