Crystal structure of the Marburg virus GP2 core domain in its postfusion conformation.
Crystal structure of the Marburg virus GP2 core domain in its postfusion conformation.
复制标题
DOI：
10.1021/bi300976m
复制
发表时间：
2012-10-02
期刊：
影响因子：
2.9
通讯作者：
Lai JR
中科院分区：
文献类型：
--
作者：
Koellhoffer JF;Malashkevich VN;Harrison JS;Toro R;Bhosle RC;Chandran K;Almo SC;Lai JR
马尔堡病毒（MARV）和埃博拉病毒（EBOV）是丝状病毒科（“丝状病毒”）的成员，其引起严重的出血热，人类病死率高达90%。丝状病毒感染需要宿主细胞和病毒膜的融合，这是一个由包膜糖蛋白（GP）介导的过程。GP含有两个亚基，表面亚基（GP 1），负责细胞附着，和跨膜亚基（GP 2），催化膜融合。GP 2胞外域含有两个七肽重复区，N-末端和C-末端（分别为NHR和NHR），其在融合过程中采用六螺旋束。这种六螺旋束的重折叠提供了克服与膜融合相关的障碍的热力学驱动力。在这里，我们报告的晶体结构的MARV GP 2核心结构域在其融合后（六螺旋束）的构象在1.9毫米分辨率。MARV GP 2核心结构域骨架构象与EBOV GP 2（先前报道）几乎相同，由一个中心NHR核心三聚体卷曲螺旋和一个插入环/螺旋-转角-螺旋片段组成。我们先前报道MARV GP 2融合后结构的稳定性是高度pH依赖性的，在较低pH下稳定性增加[Harrison，J.S.; Koellhoffer，J. K.; Dallan，K.;和Lai，J.R. Biochemistry，2012，51，2515-2525]。我们假设这种pH依赖性稳定性提供了一种构象控制机制，使得融合后六螺旋束在适当成熟的内体环境中得到促进。在本报告中，描述了这种pH依赖性稳定性的结构原理，涉及结构中段的高密度核心和表面酸性侧链阵列，称为“阴离子条带”。此外，许多表面暴露的盐桥可能有助于在低pH值下稳定融合后结构。这些结果为MARV GP 2介导的膜融合机制提供了结构见解。
Marburg virus (MARV) and Ebola virus (EBOV) are members of the family Filoviridae (‘filoviruses’) that cause severe hemorrhagic fever with human case fatality rates of up to 90%. Filovirus infection requires fusion of the host cell and virus membranes, a process that is mediated by the envelope glycoprotein (GP). GP contains two subunits, the surface subunit (GP1), which is responsible for cell attachment, and the transmembrane subunit (GP2), which catalyzes membrane fusion. The GP2 ectodomain contains two heptad repeat regions, N-terminal and C-terminal (NHR and CHR, respectively) that adopt a six-helix bundle during the fusion process. The refolding of this six-helix bundle provides the thermodynamic driving force to overcome barriers associated with membrane fusion. Here we report the crystal structure of the MARV GP2 core domain in its post-fusion (six-helix bundle) conformation at 1.9 Å resolution. The MARV GP2 core domain backbone conformation is virtually identical to that of EBOV GP2 (reported previously), and consists of a central NHR core trimeric coiled-coil packed against peripheral CHR α-helices and an intervening loop/helix-turn-helix segment. We previously reported that the stability of the MARV GP2 post-fusion structure is highly pH-dependent, with increasing stability at lower pH [Harrison, J.S.; Koellhoffer, J. K.; Chandran, K.; and Lai, J. R. Biochemistry, 2012, 51, 2515–2525]. We hypothesized that this pH-dependent stability provides a mechanism for conformational control such that the post-fusion six helix bundle is promoted in the environments of appropriately matured endosomes. In this report, a structural rationale for this pH-dependent stability is described, and involves a high-density array of core and surface acidic side chains at the midsection of the structure, termed the ‘anion stripe.’ In addition, many surface-exposed salt bridges likely contribute to stabilizing the post-fusion structure at low pH. These results provide structural insights into the mechanism of MARV GP2-mediated membrane fusion.
登录
查看更多内容
影响因子：
7.8
作者：
Harrison, Stephen C.
通讯作者：
Harrison, Stephen C.
影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.5
作者：
CARR, CM;KIM, PS
通讯作者：
KIM, PS
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M