Tertiary Structure-Function Analysis Reveals the Pathogenic Signaling Potentiation Mechanism of Helicobacter pylori Oncogenic Effector CagA
Tertiary Structure-Function Analysis Reveals the Pathogenic Signaling Potentiation Mechanism of Helicobacter pylori Oncogenic Effector CagA
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DOI：
10.1016/j.chom.2012.05.010
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发表时间：
2012-07-19
影响因子：
30.3
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Hayashi, Takeru;Senda, Miki;Hatakeyama, Masanori
幽门螺杆菌 IV 型分泌效应子 CagA 是主要的细菌毒力决定因素，对胃癌发生至关重要。在递送到胃上皮细胞后，CagA 定位于质膜的内表面，在那里它充当致病支架/中枢，混杂地招募宿主蛋白以增强致癌信号传导。我们发现 CagA 包含一个结构化的 N 端区域和一个本质上无序的 C 端区域，可指导多种蛋白质相互作用。 N 末端 CagA 片段（残基 1-876）的 X 射线晶体学分析表明该区域具有由三个离散结构域组成的结构。结构域 I 构成可移动的 CagA N 末端，而结构域 II 通过与膜磷脂酰丝氨酸相互作用将 CagA 束缚在质膜上。结构域 III 与本质上无序的 C 末端区域发生分子内相互作用，这种相互作用增强了 CagA 的致病支架/中枢功能。目前的工作为幽门螺杆菌 CagA 的病理生理/致癌作用提供了三级结构基础。
The Helicobacter pylori type IV secretion effector CagA is a major bacterial virulence determinant and critical for gastric carcinogenesis. Upon delivery into gastric epithelial cells, CagA localizes to the inner face of the plasma membrane, where it acts as a pathogenic scaffold/hub that promiscuously recruits host proteins to potentiate oncogenic signaling. We find that CagA comprises a structured N-terminal region and an intrinsically disordered C-terminal region that directs versatile protein interactions. X-ray crystallographic analysis of the N-terminal CagA fragment (residues 1-876) revealed that the region has a structure comprised of three discrete domains. Domain I constitutes a mobile CagA N terminus, while Domain II tethers CagA to the plasma membrane by interacting with membrane phosphatidylserine. Domain III interacts intramolecularly with the intrinsically disordered C-terminal region, and this interaction potentiates the pathogenic scaffold/hub function of CagA. The present work provides a tertiary-structural basis for the pathophysiological/oncogenic action of H. pylori CagA.