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Structural basis for semaphorin signalling through the plexin receptor

机译：通过plexin受体发出semaphorin信号的结构基础

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摘要

Semaphorins and their receptor plexins constitute a pleiotropic cell-signalling system that is used in a wide variety of biological processes, and both protein families have been implicated in numerous human diseases. The binding of soluble or membrane-anchored semaphorins to the membrane-distal region of the plexin ecto-domain activates plexin's intrinsic GTPase-activating protein (GAP) at the cytoplasmic region, ultimately modulating cellular adhesion behaviour. However, the structural mechanism underlying the receptor activation remains largely unknown. Here we report the crystal structures of the semaphorin 6 A (Sema6A) receptor-binding fragment and the plexin A2 (PlxnA2) ligand-binding fragment in both their pre-signalling (that is, before binding) and signalling (after complex formation) states. Before binding, the Sema6A ectodomain was in the expected 'face-to-face' homodimer arrangement, similar to that adopted by Sema3A and Sema4D, whereas PlxnA2 was in an unexpected 'head-on' homodimer arrangement. In contrast, the structure of the Sema6A-PlxnA2 signalling complex revealed a 2:2 heterotetramer in which the two PlxnA2 monomers dissociated from one another and docked onto the top face of the Sema6A homodimer using the same interface as the head-on homodimer, indicating that plexins undergo 'partner exchange'. Cell-based activity measurements using mutant ligands/ receptors confirmed that the Sema6A face-to-face dimer arrangement is physiologically relevant and is maintained throughout signalling events. Thus, homodimer-to-heterodimer transitions of cell-surface plexin that result in a specific orientation of its molecular axis relative to the membrane may constitute the structural mechanism by which the ligand-binding 'signal' is transmitted to the cytoplasmic region, inducing GAP domain rearrangements and activation.
机译：信号蛋白及其受体plexins构成了一种多效性的细胞信号传递系统，可用于多种生物学过程，并且这两种蛋白家族均涉及许多人类疾病。可溶性或膜锚定的信号量与plexin胞外域的膜远端区域的结合会在细胞质区域激活plexin的固有GTPase激活蛋白（GAP），最终调节细胞的黏附行为。然而，受体激活的基础结构机制仍然是未知的。在这里，我们报告了信号素6 A（Sema6A）受体结合片段和plexin A2（PlxnA2）配体结合片段的晶体结构，它们处于信号前（即结合前）和信号传导（复合物形成后）状态。结合前，Sema6A胞外域处于预期的“面对面”同源二聚体排列，与Sema3A和Sema4D所采用的相似，而PlxnA2处于出乎意料的“正面”同源二聚体排列。相反，Sema6A-PlxnA2信号复合物的结构显示出2：2异源四聚体，其中两个PlxnA2单体彼此解离，并使用与正面同二聚体相同的界面对接在Sema6A同二聚体的顶面上。 plexins进行“伙伴交换”。使用突变配体/受体进行的基于细胞的活性测量证实，Sema6A面对面的二聚体排列在生理上是相关的，并且在整个信号传递事件中都得到维持。因此，导致其分子轴相对于膜的特定取向的细胞表面plexin的同二聚体至异二聚体转变可能构成了结构机制，通过该机制，配体结合“信号”被传递至细胞质区域，从而诱导GAP域重排和激活。

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  • 来源
    《Nature》 |2010年第7319期|p.1123-1127|共5页
  • 作者

    Temkazu Nogi; Norihisa Yasui; Emiko Mihara; Yukiko Matsunaga; Masanori Noda; Naoya Yamashita; Toshihiko Toyofuku; Susumu Uchiyama; Yoshio Goshima; Atsushi Kumanogoh; Junichi Takagi;

  • 作者单位

    Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan,Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, W234, Chicago, Illinois 60637, USA;

    rnLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnDepartment of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnDepartment of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan;

    rnDepartment of Immunopathology, Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnDepartment of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnDepartment of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan;

    rnDepartment of Immunopathology, Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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