A Salt Bridge and Disulfide Bond within the Lassa Virus Fusion Domain Are Required for the Initiation of Membrane Fusion
A Salt Bridge and Disulfide Bond within the Lassa Virus Fusion Domain Are Required for the Initiation of Membrane Fusion
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Lassa病毒融合域中的盐桥和二硫键是启动膜融合所必需的
DOI：
10.1021/acsomega.3c08632
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发表时间：
2024-01-18
期刊：
影响因子：
4.1
通讯作者：
Lee, Jinwoo
中科院分区：
文献类型：
--
作者：
Pennington, Hallie N.;Birtles, Daniel;Shi, Zoe W.;Lee, Jinwoo
拉沙病毒（LASV）是西非特有的旧大陆沙粒病毒，感染该病毒可引起拉沙热，这是一种致命的出血热。LASV的遗传物质进入宿主细胞是其生命周期的一个组成部分。这是通过膜融合完成的，这一过程是由称为融合域（FD）的疏水序列发起的。LASV FD （G260-N295）由两个结构不同的区域组成：一个n端融合肽（FP: G260-T274）和一个内部融合环（FL: C279-N295），该融合环由一个短连接子区域（P275-Y278）连接。然而，LASV FD启动融合的分子机制尚不清楚。在这里，我们证明了LASV FD在类似于溶酶体室的pH值下采用融合性螺旋构象。此外，我们在FL中发现了与聚变有关的保守二硫键（C279和C292）和盐桥（R282和E289）。我们发现二硫键必须存在，这样FD才能与脂质双分子层结合并随后开始融合。此外，盐桥对于FD的二级结构至关重要，因此它可以在适当的方向上与脂质双分子层结合以发挥全部功能。总之，我们的研究结果表明，LASV FD优先启动融合的pH值与溶酶体相似，其机制需要一个保守的盐桥，在较小程度上，内部FL中需要一个完整的二硫键。
Infection with Lassa virus (LASV), an Old-World arenavirus that is endemic to West Africa, causes Lassa fever, a lethal hemorrhagic fever. Delivery of LASV’s genetic material into the host cell is an integral component of its lifecycle. This is accomplished via membrane fusion, a process initiated by a hydrophobic sequence known as the fusion domain (FD). The LASV FD (G260–N295) consists of two structurally distinct regions: an N-terminal fusion peptide (FP: G260–T274) and an internal fusion loop (FL: C279–N295) that is connected by a short linker region (P275–Y278). However, the molecular mechanisms behind how the LASV FD initiates fusion remain unclear. Here, we demonstrate that the LASV FD adopts a fusogenic, helical conformation at a pH akin to that of the lysosomal compartment. Additionally, we identified a conserved disulfide bond (C279 and C292) and salt bridge (R282 and E289) within the FL that are pertinent to fusion. We found that the disulfide bond must be present so that the FD can bind to the lipid bilayer and subsequently initiate fusion. Moreover, the salt bridge is essential for the secondary structure of the FD such that it can associate with the lipid bilayer in the proper orientation for full functionality. In conclusion, our findings indicate that the LASV FD preferentially initiates fusion at a pH akin to that of the lysosome through a mechanism that requires a conserved salt bridge and, to a lesser extent, an intact disulfide bond within the internal FL.
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