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Structural basis of semaphorin-plexin signalling

机译：semaphorin-plexin信号传导的结构基础

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摘要

Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNBl_(1-2)-SEMA4D_(ecto)and murine PlxnA2_(1-4)-Sema6A_(ecto)), plus unliganded structures of PlxnA2_(1-4) and Sema6A_(ecto). These structures together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.
机译：通过与plexin受体的相互作用，信号蛋白配体的细胞信号传导对于许多组织的稳态和形态发生很重要，并且由于其在神经连通性，癌症，细胞迁移和免疫反应中的作用而被广泛研究。 SEMA4D和Sema6A举例说明了两种不同的脊椎动物跨膜信号量类（4和6），它们能够分别通过两个最大的丛蛋白类B和A的成员直接发出信号。在关于plexin胞外域或其与信号灯蛋白的相互作用缺乏任何结构信息的情况下，仍无法解决细胞外特异性和控制plexin信号传导的机制。在这里，我们介绍了plexins B1和A2的信号量结合区域与信号量胞外域（人PLXNBl_（1-2）-SEMA4D_（胞外）和鼠PlxnA2_（1-4）-Sema6A_（胞外））的同源复合物的晶体结构，加上PlxnA2_（1-4）和Sema6A_（ecto）的未配体结构。这些结构以及野生型和突变蛋白的生物物理和细胞分析结果表明，信号量二聚体独立结合两个plexin分子，并且信号传导关键取决于所产生的二价2：2复合物的亲和力（单体信号量结合plexin，但不能触发信令）。结合起来，我们的数据支持一种涉及信号量稳定的plexin二聚化的细胞-细胞信号传导机制，然后可能会发生聚类，这与以前的功能数据一致。此外，通过信号素和plexin的氨基末端七叶β螺旋桨（sema）域的保守接触形成的复合物共有的通用体系结构表明，相互作用的共同方式会触发所有基于信号素-plexin的信号传导，而在sema域的叶片内或叶片之间的不同插入决定了结合特异性。

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  • 来源
    《Nature》 |2010年第7319期|p.1118-1122|共5页
  • 作者

    Bert J. C. Janssen; Ross A. Robinson; Francesc Perez-Branguli; Christian H. Bell; Kevin J. Mitchell; Christian Siebold; E. Yvonne Jones;

  • 作者单位

    Division of Structural Biology, Wellcome Trust Centre for Human genetics, University of Oxford, Oxford OX3 7BN, UK;

    rnDivision of Structural Biology, Wellcome Trust Centre for Human genetics, University of Oxford, Oxford OX3 7BN, UK;

    rnSmurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland;

    rnDivision of Structural Biology, Wellcome Trust Centre for Human genetics, University of Oxford, Oxford OX3 7BN, UK;

    rnSmurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland;

    rnDivision of Structural Biology, Wellcome Trust Centre for Human genetics, University of Oxford, Oxford OX3 7BN, UK;

    rnDivision of Structural Biology, Wellcome Trust Centre for Human genetics, University of Oxford, Oxford OX3 7BN, UK;

  • 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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