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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis for mutual relief of the Rac guanine nucleotide exchange factor D0CK2 and its partner ELM01 from their autoinhibited forms
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Structural basis for mutual relief of the Rac guanine nucleotide exchange factor D0CK2 and its partner ELM01 from their autoinhibited forms

机译：Rac鸟嘌呤核苷酸交换因子D0CK2及其伴侣ELM01从自身抑制形式相互缓解的结构基础

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摘要

D0CK2, a hematopoietic cell-specific, atypical guanine nucleotide exchange factor, controls lymphocyte migration through ras-related C3 botulinum toxin substrate (Rac) activation. Dedicator of cytokinesis 2-engulfment and cell motility protein 1 (DOCK2·ELMO1) complex formation is required for D0CK2-mediated Rac signaling. In this study, we identified the N-terminal 177-residue fragment and the C-terminal 196-residue fragment of human D0CK2 and ELM01, respectively, as the mutual binding regions, and solved the crystal structure of their complex at 2.1-A resolution. The C-terminal Pro-rich tail of ELM01 winds around the Src-homology 3 domain of DOCK2, and an intermolecular five-helix bundle is formed. Overall, the entire regions of both D0CK2 and ELM01 assemble to create a rigid structure, which is required for the DOCK2·ELMO1 binding, as revealed by mutagenesis. Intriguingly, the DOCK2·ELMO1 interface hydrophobically buries a residue which, when mutated, reportedly relieves DOCK180 from autoinhibition. We demonstrated that the ELMO-interacting region and the DOCK-homology region 2 guanine nucleotide exchange factor domain of DOCK2 associate with each other for the autoinhibition, and that the assembly with ELMO1 weakens the interaction, relieving DOCK2 from the autoinhibition. The interactions between the N- and C-terminal regions of ELMO1 reportedly cause its autoinhibition, and binding with a DOCK protein relieves the autoinhibition for ras homolog gene family, member G binding and membrane localization. In fact, the DOCK2·-ELMO1 interface also buries the ELMO1 residues required for the autoinhibition within the hydrophobic core of the helix bundle. Therefore, the present complex structure reveals the structural basis by which DOCK2 and ELM01 mutually relieve their autoinhibition for the activation of Rac1 for lymphocyte chemotaxis.
机译：D0CK2是造血细胞特异性的非典型鸟嘌呤核苷酸交换因子，可通过ras相关的C3肉毒毒素底物（Rac）激活来控制淋巴细胞的迁移。 D0CK2介导的Rac信号传导需要细胞分裂2吞噬和细胞运动蛋白1（DOCK2·ELMO1）复合物形成的指示剂。在这项研究中，我们确定了人D0CK2和ELM01的N端177个残基片段和C端196个残基片段为相互结合区域，并以2.1-A的分辨率解析了它们的复合物的晶体结构。 ELM01的C端富含Pro的尾巴缠绕在DOCK2的Src同源3域上，并形成了分子间的五螺旋束。总体而言，D0CK2和ELM01的整个区域组装在一起以创建一个刚性结构，这是诱变所揭示的DOCK2·ELMO1结合所必需的。有趣的是，DOCK2·ELMO1界面疏水性掩埋了一个残基，据报道该残基突变后可解除DOCK180的自抑制作用。我们证明了DOCM2的ELMO相互作用区域和DOCK同源性区域2鸟嘌呤核苷酸交换因子域相互关联以实现自抑制作用，并且与ELMO1的装配减弱了相互作用，从而减轻了DOCK2的自抑制作用。据报道，ELMO1的N端和C端区域之间的相互作用导致其自动抑制，与DOCK蛋白的结合可缓解ras同源基因家族，G成员结合和膜定位的自动抑制。实际上，DOCK2·-ELMO1接口还在螺旋束的疏水核内埋有自抑制所需的ELMO1残基。因此，本发明的复杂结构揭示了DOCK2和ELM01通过相互解除它们对淋巴细胞趋化性的Rac1活化的自抑制作用的结构基础。

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  • 作者

    Kyoko Hanawa-Suetsugu; Mutsuko Kukimoto-Niino; Chiemi Mishima-Tsumagari; Ryogo Akasaka; Noboru Ohsawa; Shun-ichi Sekine; Takuhiro Ito; Naoya Tochio; Seizo Koshiba; Takanori Kigawa; Takaho Terada; Mikako Shirouzu; Akihiko Nishikimi; Takehito Uruno; Tomoya Katakai; Tatsuo Kinashi; Daisuke Kohda; Yoshinori Fukui; Shigeyuki Yokoyama;

  • 作者单位

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0075, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Tokyo Institute of Technology, 4259 Nagatsuta, Midori, Yokohama 226-8502, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0075, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan;

    Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0075, Japan,Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan,Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan;

    Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;

    Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka 570-8506, Japan;

    Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka 570-8506, Japan;

    Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;

    Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0075, Japan,Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan,Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan;

    RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan,Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 102-0075, Japan,Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan;

  • 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

    X-ray crystallography; NMR; protein complex; CDM proteins; immunology;

    机译：X射线晶体学;NMR;蛋白质复合物CDM蛋白;免疫学;

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