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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach
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Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach

机译：结合计算和实验方法生产的TRPP2 / PKD1 C末端卷曲螺旋复合物的结构模型

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摘要

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in TRPP2 and PKD1, which form an ion channel/receptor complex containing three TRPP2 and one PKD1. A TRPP2 C-terminal coiled-coil trimer, critical for the assembly of this complex, associates with a single PKD1 C-terminal coiled-coil. Many ADPKD pathogenic mutations result in the abolishment of the TRPP2/PKD1 coiled-coil complex. To gain molecular and functional insights into this heterotetrameric complex, we computationally constructed a structural model by using a two-step docking strategy, based on a known crystal structure of the TRPP2 coiled-coil trimer. The model shows that this tetrameric complex has a novel di-trimer configuration: An upstream trimer made of three TRPP2 helices and a downstream trimer made of two TRPP2 helices and one PKD1 helix. Mutagenesis and biochemical analysis identified critical TRPP2/ PKD1 interface contacts essential for the heteromeric coiled-coil complex. Mutation of these interface positions in the full-length proteins showed that these interactions were critical for the assembly of the full-length complex in cells. Our results provide a means to specifically weaken the TRPP2 and PKD1 association, thus facilitating future in vitro and in vivo studies on the functional importance of this association.
机译：常染色体显性遗传性多囊肾疾病（ADPKD）是由TRPP2和PKD1中的突变引起的，它们形成了包含三个TRPP2和一个PKD1的离子通道/受体复合物。对于该复合物的组装至关重要的TRPP2 C末端螺旋线圈三聚体与单个PKD1 C末端螺旋线圈关联。许多ADPKD致病性突变导致废除TRPP2 / PKD1卷曲螺旋复合体。为了获得对该异四聚体复合物的分子和功能方面的见解，我们基于TRPP2卷曲螺旋三聚体的已知晶体结构，通过两步对接策略以计算方式构建了结构模型。模型显示该四聚体复合物具有新颖的二聚体构型：由三个TRPP2螺旋制成的上游三聚体和由两个TRPP2螺旋和一个PKD1螺旋制成的下游三聚体。诱变和生化分析确定了关键的TRPP2 / PKD1界面接触对于异源卷曲螺旋复合物必不可少。全长蛋白质中这些界面位置的突变表明，这些相互作用对于全长复合物在细胞中的组装至关重要。我们的结果提供了一种专门减弱TRPP2和PKD1关联的方法，从而促进了对该关联的功能重要性的未来体外和体内研究。

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    Jiang Zhu; Yong Yu; Maximilian H. Ulbrich; Ming-hui Li; Ehud Y. lsacoff; Barry Honig; Jian Yang;

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    Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032,Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;

    Department of Biological Sciences, Columbia University, New York, NY 10027;

    Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720,Institute of Physiology and Center for Biological Signaling Studies, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany;

    Department of Biological Sciences, Columbia University, New York, NY 10027;

    Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720,Material Science and Physical Bioscience Divisions, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;

    Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032;

    Department of Biological Sciences, Columbia University, New York, NY 10027;

  • 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);
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