PDF(Pubmed)
Abstract：
Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses.
摘要：
东方马脑炎病毒(EEEV)是感染人类毒性最强的甲病毒,许多幸存者会出现神经系统后遗症，包括瘫痪和智力残疾。甲病毒刺突蛋白包含糖蛋白E2和E1的异二聚体的三聚体,其在进入期间介导与细胞受体的结合以及病毒和宿主细胞膜的融合。我们最近确定了极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER2）作为EEEV和远缘相关的甲病毒的细胞受体，Semliki森林病毒（SFV）。这里,我们使用单粒子冷冻电子显微镜（cryo-EM）来确定与VLDLR配体结合域结合的EEEV和SFV刺突糖蛋白的结构，并发现EEEV和SFV通过不同的结合模式与相同的细胞受体相互作用。我们的研究表明，LDLR相关蛋白通过具有灵活结合模式的非常小的足迹与病毒刺突蛋白相互作用的能力导致获得LDLR相关蛋白作为不同病毒组的细胞受体的低进化障碍。
