Yang Decheng, Wang Nan, Du Bingchen, Sun Zhenzhao, Wang Shida, He Xijun, Wang Jinyue, Zheng Tao, Chen Yutao, Wang Xiangxi, Wang Jingfei
State Key Laboratory for Animal Disease Control and Prevention & National Data Center for Animal Infectious Diseases, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.
CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
PLoS Pathog. 2024 Dec 20;20(12):e1012770. doi: 10.1371/journal.ppat.1012770. eCollection 2024 Dec.
The Very Low-Density Lipoprotein Receptor (VLDLR) is an entry receptor for the prototypic alphavirus Semliki Forest Virus (SFV). However, the precise mechanisms underlying the entry of SFV into cells mediated by VLDLR remain unclear. In this study, we found that of the eight class A (LA) repeats of the VLDLR, only LA2, LA3, and LA5 specifically bind to the native SFV virion while synergistically promoting SFV cell attachment and entry. Furthermore, the multiple cryo-electron microscopy structures of VLDLR-SFV complexes and mutagenesis studies have demonstrated that under physiological conditions, VLDLR primarily binds to E1-DIII of site-1, site-2, and site-1' at the twofold symmetry axes of SFV virion through LA2, LA3, and LA5, respectively. These findings unveil a novel mechanism for viral entry mediated by receptors, suggesting that conformational transitions in VLDLR induced by multivalent binding of LAs facilitate cellular internalization of SFV, with significant implications for the design of antiviral therapeutics.
极低密度脂蛋白受体（VLDLR）是原型甲病毒塞姆利基森林病毒（SFV）的一种进入受体。然而，VLDLR介导SFV进入细胞的精确机制仍不清楚。在本研究中，我们发现VLDLR的八个A类（LA）重复序列中，只有LA2、LA3和LA5能特异性结合天然SFV病毒粒子，同时协同促进SFV细胞附着和进入。此外，VLDLR-SFV复合物的多个冷冻电子显微镜结构和诱变研究表明，在生理条件下，VLDLR主要分别通过LA2、LA3和LA5与SFV病毒粒子双重对称轴上的位点1、位点2和位点1'的E1-DIII结合。这些发现揭示了一种由受体介导的病毒进入新机制，表明LA的多价结合诱导的VLDLR构象转变促进了SFV的细胞内化，这对抗病毒治疗药物的设计具有重要意义。
