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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin
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Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin

机译：幽门螺杆菌癌蛋白CagA与β1整合素相互作用的结构见解

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摘要

Infection with the gastric pathogen Helicobacter pylori is a risk factor for the development of gastric cancer. Pathogenic strains of H. pylori carry a type IV secretion system (T4SS) responsible for the injection of the oncoprotein CagA into host cells. H. pylori and its cag-T4SS exploit α5β1 integrin as a receptor for CagA trans-location. Injected CagA localizes to the inner leaflet of the host cell membrane, where it hijacks host cell signaling and induces cyto-skeleton reorganization. Here we describe the crystal structure of the N-terminal ～100-kDa subdomain of CagA at 3.6 A that unveils a unique combination of folds. The core domain of the protein consists of an extended single-layer (β-sheet stabilized by two independent helical subdomains. The core is followed by a long helix that forms a four-helix helical bundle with the C-terminal domain. Mapping of conserved regions in a set of CagA sequences identified four conserved surface-exposed patches (CSP1-4), which represent putative hot-spots for protein-protein interactions. The proximal part of the single-layer β-sheet, covering CSP4, is involved in specific binding of CagA to the β1 integrin, as determined by yeast two-hybrid and in vivo competition assays in H. pylori cell-culture infection studies. These data provide a structural basis for the first step of CagA internalization into host cells and suggest that CagA uses a previously undescribed mechanism to bind β1 integrin to mediate its own translocation.
机译：胃病原体感染幽门螺杆菌是胃癌发展的危险因素。幽门螺杆菌的致病性菌株携带负责将癌蛋白CagA注入宿主细胞的IV型分泌系统（T4SS）。幽门螺杆菌及其cag-T4SS利用α5β1整联蛋白作为CagA易位的受体。注射的CagA定位于宿主细胞膜的内部小叶，在此劫持宿主细胞信号并诱导细胞骨架重组。在这里，我们描述了在3.6 A时CagA的N端〜100 kDa子域的晶体结构，揭示了独特的折叠组合。蛋白质的核心结构域由一个扩展的单层结构（由两个独立的螺旋亚结构域稳定的β-折叠层组成）。核心之后是一个长螺旋，该螺旋与C端结构域形成一个四螺旋螺旋束。在一组CagA序列的区域中，鉴定出四个保守的表面暴露斑块（CSP1-4），它们代表了蛋白质-蛋白质相互作用的假定热点，单层β-折叠的近端部分覆盖了CSP4，幽门螺杆菌细胞培养感染研究中通过酵母双杂交和体内竞争试验确定了CagA与β1整联蛋白的特异性结合，这些数据为CagA内化进入宿主细胞的第一步提供了结构基础，并表明CagA使用先前未描述的机制结合β1整联蛋白来介导其自身的易位。

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  • 作者

    Burcu Kaplan-Tuerkoez; Luisa F. Jimenez-Soto; Cyril Dian; Claudia Ertl; Han Remaut; Arthur Louche; Tommaso Tosi; Rainer Haas; Laurent Terradot;

  • 作者单位

    Centre National de la Recherche Scientifique-Ligue Contre le Cancer, ATIP Avenir Group, Institut de Biologie et Chimie des Proteines, Unite Mixte de Recherche 5086, Universite Lyon, Lyon F-69367, France;

    Centre National de la Recherche Scientifique-Ligue Contre le Cancer, ATIP Avenir Group, Institut de Biologie et Chimie des Proteines, Unite Mixte de Recherche 5086, Universite Lyon, Lyon F-69367, France;

    lnstitut de Biologie Structural J. P. Ebel, F-38027 Grenoble Cedex, France;

    Max von Pettenkofer-lnstitut fur Hygiene und Medizinische Mikrobiologie, Department of Bacteriology, Ludwig-Maximilians-Universitaet, D-80336 Munich, Germany;

    Structural Biology Brussels, Vrije Universiteit Brussels, 1050 Brussels, Belgium,Structural and Molecular Microbiology, Vlaams Instituut voor Biotechnologie (VIB) Department of Structural Biology, VIB, 1050 Brussels, Belgium;

    Centre National de la Recherche Scientifique-Ligue Contre le Cancer, ATIP Avenir Group, Institut de Biologie et Chimie des Proteines, Unite Mixte de Recherche 5086, Universite Lyon, Lyon F-69367, France;

    lnstitut de Biologie Structural J. P. Ebel, F-38027 Grenoble Cedex, France;

    Max von Pettenkofer-lnstitut fur Hygiene und Medizinische Mikrobiologie, Department of Bacteriology, Ludwig-Maximilians-Universitaet, D-80336 Munich, Germany;

    Centre National de la Recherche Scientifique-Ligue Contre le Cancer, ATIP Avenir Group, Institut de Biologie et Chimie des Proteines, Unite Mixte de Recherche 5086, Universite Lyon, Lyon F-69367, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    virulence factor; X-ray crystallography; oncogene; pathogenicity; gastric ulcer;

    机译：毒力因子;X射线晶体学;癌基因致病性胃溃疡;

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