Structural basis for semaphorin signalling through the plexin receptor
Structural basis for semaphorin signalling through the plexin receptor
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DOI：
10.1038/nature09473
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发表时间：
2010-10-28
期刊：
影响因子：
64.8
通讯作者：
Takagi, Junichi
中科院分区：
文献类型：
--
作者：
Nogi, Terukazu;Yasui, Norihisa;Takagi, Junichi
信号素及其受体网络蛋白构成了一个广泛应用于多种生物过程的多效性细胞信号传递系统，这两个蛋白家族都与许多人类疾病有关(1-4)。可溶性或膜锚定的信号素与网织蛋白胞外区的膜-远端区域结合，激活网织蛋白在细胞质区域的内在GTP酶激活蛋白(GAP)，最终调节细胞黏附行为(5)。然而，受体激活的结构机制在很大程度上仍不清楚。在这里，我们报道了信号素6A(Sema6A)受体结合片段和Plexin A2(PlxnA2)配体结合片段在信号传递前(即结合前)和信号传递(复合体形成后)两种状态下的晶体结构。在结合之前，Sema6A的胞外结构域处于预期的“面对面”同源二聚体排列，类似于Sema3A和Sema4D采用的同源二聚体排列，而PlxnA2则处于意想不到的“正面”同源二聚体排列。相反，Sema6A-PlxnA2信号复合体的结构显示了2：2的异四聚体，其中两个PlxnA2单体彼此解离，并使用与正面同源二聚体相同的界面停靠在Sema6A同源二聚体的顶部，这表明丛状蛋白经历了“伙伴交换”。使用突变配体/受体的细胞活性测量证实，Sema6A面对面的二聚体排列是生理相关的，并在整个信号事件中保持不变。因此，细胞-表面丛蛋白的同源二聚体到异源二聚体的转变导致其分子轴相对于膜的特定方向可能构成了结构机制，通过该结构机制，配体结合的信号被传递到细胞质区域，诱导间隙结构域重排和激活。
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(1-4). 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(5). However, the structural mechanism underlying the receptor activation remains largely unknown. Here we report the crystal structures of the semaphorin 6A (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.