Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1.
Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1.
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DOI：
10.1128/jvi.01048-18
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发表时间：
2019-01-01
影响因子：
5.4
通讯作者：
Bowden TA
中科院分区：
文献类型：
--
作者：
Pryce R;Ng WM;Zeltina A;Watanabe Y;El Omari K;Wagner A;Bowden TA
沙粒病毒科中的基因和地理上多样的病毒群包括许多能够引起致命性出血热的人畜共患病原体。沙粒病毒包膜上的多亚基GPC糖蛋白刺突复合物是种嗜性的关键决定因素，也是宿主体液免疫应答的主要靶点。在这里，我们表明，受体结合GP1子组件的GPC穗旧世界，但不是新世界沙粒病毒采用了独特的，pH值无关的构象在没有同源GP2。我们的分析提供了一种基于结构的方法来理解这些治疗上重要的靶点所采样的离散构象类，为开发类似于成熟病毒体表面上所呈现的GPC的沙粒病毒糖蛋白免疫原提供了策略。新、旧世界沙粒病毒从啮齿动物宿主中的出现持续威胁着人类健康。沙粒病毒糖蛋白刺突复合物（GPC）的GP1亚基介导宿主细胞识别，是跨物种传播的重要决定因素。以前的旧世界沙粒病毒GP1糖蛋白，单独的和在复杂的同源GP2亚基的结构分析表明，GP1采用两种不同的构象状态区分的螺旋区域的分子的方向的差异。在这里，通过旧世界洛伊河病毒和新世界白水阿罗约病毒的GP1糖蛋白结构的比较研究，我们表明，这些重排仅限于旧世界沙粒病毒，而不是诱导的pH值变化，是与病毒内体运输。我们对沙粒病毒GP1的基于结构的系统发育分析为理解这些治疗重要靶点所采用的离散结构类别提供了蓝图。重要性沙粒病毒科中基因和地理分布多样的病毒群包括许多能够引起致命性出血热的人畜共患病原体。沙粒病毒包膜上的多亚基GPC糖蛋白刺突复合物是种嗜性的关键决定因素，也是宿主体液免疫应答的主要靶点。在这里，我们表明，受体结合GP1子组件的GPC穗旧世界，但不是新世界沙粒病毒采用了独特的，pH值无关的构象在没有同源GP2。我们的分析提供了一种基于结构的方法来理解这些治疗上重要的靶点所采样的离散构象类，为开发类似于成熟病毒体表面上所呈现的GPC的沙粒病毒糖蛋白免疫原提供了策略。
The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface. The emergence of Old and New World arenaviruses from rodent reservoirs persistently threatens human health. The GP1 subunit of the envelope-displayed arenaviral glycoprotein spike complex (GPC) mediates host cell recognition and is an important determinant of cross-species transmission. Previous structural analyses of Old World arenaviral GP1 glycoproteins, alone and in complex with a cognate GP2 subunit, have revealed that GP1 adopts two distinct conformational states distinguished by differences in the orientations of helical regions of the molecule. Here, through comparative study of the GP1 glycoprotein architectures of Old World Loei River virus and New World Whitewater Arroyo virus, we show that these rearrangements are restricted to Old World arenaviruses and are not induced solely by the pH change that is associated with virus endosomal trafficking. Our structure-based phylogenetic analysis of arenaviral GP1s provides a blueprint for understanding the discrete structural classes adopted by these therapeutically important targets. IMPORTANCE The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface.