Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
PLoS Pathog. 2022 Jun 29;18(6):e1010435. doi: 10.1371/journal.ppat.1010435. eCollection 2022 Jun.
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.
疱疹病毒进入时的膜融合是由病毒融合蛋白 gB 通过某种方式与其伴侣蛋白 gH 激活来完成的。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、抑制性夹，使 gB 保持在预融合构象。但是 gH 如何释放 gBCTD 夹尚不清楚。在这里，我们从典型的单纯疱疹病毒 1 中鉴定了 gB 和 gH 中的两个新的调节元件：gBCTD 中的表面口袋和 gH 细胞质尾部的残基 V831。突变和结构建模表明 gH V831 与 gB 口袋相互作用。gB 口袋位于相邻原体之间界面的上方，我们假设 gH V831 楔入口袋会将原体推开，从而释放抑制夹。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保守，这种激活机制可能被其他 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融合蛋白活性方面的核心作用。
