Herpes Simplex Virus 1 Entry Glycoproteins Form Complexes before and during Membrane Fusion.
Herpes Simplex Virus 1 Entry Glycoproteins Form Complexes before and during Membrane Fusion.
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作者：
疱疹病毒--导致持续感染的普遍病原体--具有一些最复杂的细胞进入机制。典型单纯疱疹病毒1型(HSV-1)的进入需要Gb、Gd、Gh和Gl四种糖蛋白的协同作用。目前的模型假设，糖蛋白在受体结合之前不相互作用，Gd与其受体的结合导致了一系列连续的成对相互作用，首先激活Gh/Gl复合体，然后激活Gb，病毒FusoGen。但这些糖蛋白如何相互作用仍未解决。在这里，使用定量分裂荧光素酶方法，我们证明了成对的HSV-1糖蛋白复合体在融合前形成，在融合过程中以稳定的水平相互作用，并且不依赖于细胞受体的存在。基于我们的发现，我们提出了一个修正的HSV-1进入的“构象级联”模型。我们假设，在融合前，所有4种糖蛋白都组装成一个复合体，Gh/g1位于Gd和Gb之间。一旦Gd与同源受体结合，该复合体中的糖蛋白的接近允许激活信号通过连续的构象变化从受体激活的Gd到Gh/Gl再到Gb，最终触发Gb的融合重折叠。我们的结果也强调了以前未被认可的跨膜和胞浆结构域对糖蛋白相互作用和融合的贡献。类似的原理可以在其他多组分病毒进入系统中发挥作用，这里使用的分裂荧光素酶方法是研究这些系统和各种其他系统中蛋白质-蛋白质相互作用的强大工具。
Herpesviruses—ubiquitous pathogens that cause persistent infections—have some of the most complex cell entry mechanisms. Entry of the prototypical herpes simplex virus 1 (HSV-1) requires coordinated efforts of 4 glycoproteins, gB, gD, gH, and gL. The current model posits that the glycoproteins do not interact before receptor engagement and that binding of gD to its receptor causes a “cascade” of sequential pairwise interactions, first activating the gH/gL complex and subsequently activating gB, the viral fusogen. But how these glycoproteins interact remains unresolved. Here, using a quantitative split-luciferase approach, we show that pairwise HSV-1 glycoprotein complexes form before fusion, interact at a steady level throughout fusion, and do not depend on the presence of the cellular receptor. Based on our findings, we propose a revised “conformational cascade” model of HSV-1 entry. We hypothesize that all 4 glycoproteins assemble into a complex before fusion, with gH/gL positioned between gD and gB. Once gD binds to a cognate receptor, the proximity of the glycoproteins within this complex allows for efficient transmission of the activating signal from the receptor-activated gD to gH/gL to gB through sequential conformational changes, ultimately triggering the fusogenic refolding of gB. Our results also highlight previously unappreciated contributions of the transmembrane and cytoplasmic domains to glycoprotein interactions and fusion. Similar principles could be at play in other multicomponent viral entry systems, and the split-luciferase approach used here is a powerful tool for investigating protein-protein interactions in these and a variety of other systems.
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DOI：
10.1073/pnas.0707452104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Atanasiu, Doina;Whitbeck, J. Charles;Eisenberg, Roselyn J.
通讯作者：
Eisenberg, Roselyn J.
影响因子：
6.7
作者：
Di Giovine P;Settembre EC;Bhargava AK;Luftig MA;Lou H;Cohen GH;Eisenberg RJ;Krummenacher C;Carfi A
通讯作者：
Carfi A
影响因子：
16
作者：
Carfí, A;Willis, SH;Wiley, DC
通讯作者：
Wiley, DC
影响因子：
5.4
作者：
Atanasiu, Doina;Saw, Wan Ting;Eisenberg, Roselyn J.
通讯作者：
Eisenberg, Roselyn J.
影响因子：
6.4
作者：
Atanasiu D;Cairns TM;Whitbeck JC;Saw WT;Rao S;Eisenberg RJ;Cohen GH
通讯作者：
Cohen GH