Structural basis of semaphorin-plexin signalling.
Structural basis of semaphorin-plexin signalling.
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作者：
通过与丛蛋白受体相互作用的脑信号蛋白配体的细胞-细胞信号传导对于许多组织的稳态和形态发生是重要的，并且因其在神经连接、癌症、细胞迁移和免疫应答中的作用而被广泛研究。SEMA 4 D和Sema 6 A是两种不同的脊椎动物跨膜信号蛋白类（4和6），它们能够分别通过两种最大的丛蛋白类B和A的成员直接信号传导。在没有任何关于丛蛋白胞外域或其与信号蛋白的相互作用的结构信息的情况下，控制丛蛋白信号传导的细胞外特异性和机制仍然没有得到解决。在这里，我们提出了同源复合物的神经丛蛋白B1和A2与脑信号蛋白胞外域（人PLXNB 11 -2-SEMA 4Decto和小鼠PlxnA 21 -4-Sema 6Aecto）的脑信号蛋白结合区域的晶体结构，加上PlxnA 21 -4和Sema 6Aecto的未配体结构。这些结构，连同野生型和突变蛋白的生物物理和细胞分析，揭示了脑信号蛋白二聚体独立地结合两个丛蛋白分子，信号传导是严重依赖于所得的二价2：2复合物的亲合力（单体脑信号蛋白结合丛蛋白，但未能触发信号传导）。结合起来，我们的数据有利于细胞-细胞信号传导机制，涉及脑信号蛋白稳定丛蛋白二聚化，可能其次是聚类，这是与以前的功能数据一致。此外，通过脑信号蛋白和丛蛋白的氨基末端七叶β推进器（sema）结构域的保守接触形成的复合物的共享的通用结构表明，共同的相互作用模式触发所有基于脑信号蛋白-丛蛋白的信号传导，而sema结构域的叶片内或叶片之间的不同插入决定结合特异性。
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 PLXNB11–2–SEMA4Decto and murine PlxnA21–4–Sema6Aecto), plus unliganded structures of PlxnA21–4 and Sema6Aecto. 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.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
5.8
作者：
Gouet, P;Courcelle, E;Métoz, F
通讯作者：
Métoz, F
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC