A surface pocket in the cytoplasmic domain of the herpes simplex virus fusogen gB controls membrane fusion.
A surface pocket in the cytoplasmic domain of the herpes simplex virus fusogen gB controls membrane fusion.
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DOI：
10.1371/journal.ppat.1010435
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发表时间：
2022-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
疱疹病毒侵入过程中的膜融合是由病毒FusoGen GB以某种方式被其伴侣蛋白Gh激活而完成的。GB的融合活性受其细胞质(或病毒内)结构域(GBCTD)的控制，根据目前的模型，gBCTD是一个三聚体抑制钳，在预融合构象中抑制GB。但GH如何释放gBCTD钳子尚不清楚。在这里，我们从典型的单纯疱疹病毒1中发现了Gb和Gh内的两个新的调节元件：gBCTD内的一个表面袋和Gh细胞质尾部内的残基V831。突变和结构模拟表明Gh V831与GB口袋相互作用。GB口袋位于相邻原型之间的界面上方，我们假设Gh V831楔子插入口袋中有助于推动原型分离，从而释放抑制钳。通过这种方式，Gh激活了Gb的融合活性。GB和Gh在所有疱疹病毒中都是保守的，这种激活机制可以被其他gB同源物使用。我们提出的机制强调了细胞质区域在调节病毒FusoGen活性方面的中心作用。单纯疱疹病毒1型(HSV-1)使超过一半的人终身感染，并导致从口腔或生殖器溃疡到失明和脑部炎症等各种疾病。目前还没有疫苗或根治疗法。要感染细胞，HSV-1必须首先通过将其脂膜与靶细胞的膜结合来穿透它们。这一过程需要几种病毒和细胞蛋白的共同作用，特别是病毒糖蛋白B和H(Gb和Gh)。GH被认为激活了GB的融合功能，但这两种蛋白质如何相互作用尚不清楚。在这里，通过突变分析，我们在Gb和Gh的细胞质区域中发现了两个新的功能元件：Gb中的一个表面袋和Gh中的一个残基，这两个元件对膜融合都是重要的。基于结构模拟，我们认为GB口袋是Gh残基的结合部位，它们之间的相互作用激活了GB导致膜融合。这些发现扩展了我们对HSV-1膜融合机制的认识。从机制上了解HSV-1的进入对于了解其发病机制和开发预防感染的新策略是必不可少的。
Membrane fusion during the entry of herpesviruses is carried out by the viral fusogen gB that is activated by its partner protein gH in some manner. The fusogenic activity of gB is controlled by its cytoplasmic (or intraviral) domain (gBCTD) and, according to the current model, the gBCTD is a trimeric, inhibitory clamp that restrains gB in the prefusion conformation. But how the gBCTD clamp is released by gH is unclear. Here, we identified two new regulatory elements within gB and gH from the prototypical herpes simplex virus 1: a surface pocket within the gBCTD and residue V831 within the gH cytoplasmic tail. Mutagenesis and structural modeling suggest that gH V831 interacts with the gB pocket. The gB pocket is located above the interface between adjacent protomers, and we hypothesize that insertion of the gH V831 wedge into the pocket serves to push the protomers apart, which releases the inhibitory clamp. In this manner, gH activates the fusogenic activity of gB. Both gB and gH are conserved across all herpesviruses, and this activation mechanism could be used by other gB homologs. Our proposed mechanism emphasizes a central role for the cytoplasmic regions in regulating the activity of a viral fusogen. Herpes simplex virus 1 (HSV-1) establishes lifelong infections in over a half of people and causes diseases ranging from oral or genital sores to blindness and brain inflammation. No vaccines or curative treatments are currently available. To infect cells, HSV-1 must first penetrate them by merging its lipid envelope with the membrane of the target cell. This process requires the collective actions of several viral and cellular proteins, notably, viral glycoproteins B and H (gB and gH). gH is thought to activate the fusogenic function of gB, but how the two proteins interact is unclear. Here, using mutational analysis, we have identified two new functional elements within the cytoplasmic regions of gB and gH: a surface pocket in gB and a single residue in gH, both of which are important for membrane fusion. Based on structural modeling, we propose that the gB pocket is the binding site for the gH residue, and that their interaction activates gB to cause membrane fusion. These findings extend our knowledge of the HSV-1 membrane fusion mechanism. Mechanistic understanding of HSV-1 entry is essential for understanding its pathogenesis and developing new strategies to prevent infections.
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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：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
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：
5.4
作者：
CAL, WH;GU, BH;PERSON, S
通讯作者：
PERSON, S
影响因子：
16
作者：
Carfí, A;Willis, SH;Wiley, DC
通讯作者：
Wiley, DC