Structural insights into VLDLR recognition by western equine encephalitis virus

作者：Shengjian Liang, Zhili Xu, Xiaoke Liu, Yan Yang, Lixin Zhao, Chongling Hu, Jichao Hou, Zhenyu Wei, Yan Zhang, Donghan Li, Yang Jin-Wei, Jiayi Zhang, Jianzhong Bi, Yan‐Yi Wang, Zhiyong Lou · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-66330-6 · 被引用次数：1 · 研究领域：Mosquito-borne diseases and control、Viral Infections and Outbreaks Research、HIV Research and Treatment

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 and 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 E2E181K or E2E81K 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. Receptor engagement is a determinant of alphavirus entry. This work reveals how Western Equine Encephalitis Virus uses very-low-density lipoprotein receptor (VLDLR) to invade our cells and finds that a single polymorphism in the E2 glycoprotein determines the receptor’s tropism.