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Structure-Function Analysis of Herpesvirus Glycoprotein H

疱疹病毒糖蛋白H的结构-功能分析

基本信息

批准号：
203064123
负责人：
Professor Dr. Thomas C. Mettenleiter
金额：
--
依托单位：
Institut für molekulare Virologie und Zellbiologie (IMVZ)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/203064123?language=en
关键词：
Structure Function Analysis Herpesvirus Glycoprotein

项目摘要

Herpesviruses infect cells using a machinery of receptor-binding components and the fusion-inducing complex. Whereas receptor-binding primarily involves subfamily-specific proteins, such as alphaherpesvirus glycoprotein gD, proteins involved in fusion between virion envelope and cellular plasma membrane are conserved throughout the Herpesviridae. These include gB whose structure is similar to that of the fusogenic G protein of vesicular stomatitis virus, and a heterodimeric complex of gH and gL. Based on crystal structures of gH proteins of three herpesviruses which became available recently, in the first period we performed site-directed mutagenesis to analyze the contributions of different domains and structural features of gH to fusion including a mobile flap which may shield or expose a hydrophobic surface and a syntaxin-like bundle. In a second approach we used reversion analysis of gL-deleted pseudorabies virus to select for compensatory mutations which yielded information on the regulation of the fusion process. The goal in this second period of the project is to continue these studies and to specifically analyze the interaction between the alphaherpesvirus glycoproteins involved in membrane fusion, i.e. gD, gH and gB. We use the well-characterized alphaherpesvirus PrV as a model since it specifies several attractive phenotypes. (i) PrV is able to mediate membrane fusion without the receptor binding component gD in transient fusion assays, in gD-independent infectivity, and in direct cell-to-cell spread; (ii) PrV can mediate efficient membrane fusion without gL in the presence of compensatory mutations in gB and/or gD and gH; (iii) structural information on gH as well as gB is available.

疱疹病毒利用受体结合组分和融合诱导复合物的机制感染细胞。尽管受体结合主要涉及亚家族特异性蛋白质，如α疱疹病毒糖蛋白gD，但参与病毒体包膜和细胞质膜之间融合的蛋白质在整个疱疹病毒科中是保守的。这些包括gB，其结构类似于水泡性口炎病毒的融合G蛋白，以及gH和gL的异二聚体复合物。基于最近获得的三种疱疹病毒gH蛋白的晶体结构，在第一阶段，我们进行了定点突变，以分析gH的不同结构域和结构特征对融合的贡献，包括一个移动的瓣，可以屏蔽或暴露疏水表面和一个突触融合蛋白样束。在第二种方法中，我们使用gL缺失的伪狂犬病病毒的回复分析来选择补偿突变，其产生关于融合过程的调节的信息。该项目第二阶段的目标是继续这些研究，并具体分析参与膜融合的α疱疹病毒糖蛋白（即gD、gH和gB）之间的相互作用。我们使用良好的特性的α疱疹病毒PrV作为模型，因为它指定了几个有吸引力的表型。(i)PrV能够介导膜融合没有受体结合组分gD在瞬时融合试验中，在gD-独立的感染性，并在直接的细胞到细胞的传播;（ii）PrV可以介导有效的膜融合没有gL在gB和/或gD和gH的补偿突变的存在下;（iii）gH以及gB的结构信息是可用的。