Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein
Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein
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DOI：
10.1523/jneurosci.5646-07.2008
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发表时间：
2008-02-27
影响因子：
5.3
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
--
作者：
Schmidt, Eric F.;Shim, Sang-Ohk;Strittmatter, Stephen M.
神经毡蛋白（Plexin，Plex）受体的信号素激活在神经元发育过程中提供轴突导向。两个细胞质蛋白家族，坍塌反应调节蛋白（CRMPs）和与CasL相互作用的分子（MICALs），都与神经毡蛋白的功能有关。CRMP和MICAL信号传导之间的关系尚未明确，神经毡蛋白激活MICAL的机制也不清楚。在此，我们表明CRMP和MICAL存在物理关联，并且信号素信号传导促进这种关联。MICAL的酶活性受到其C末端结构域的抑制。CRMP和神经毡蛋白与MICAL的非酶结构域和酶结构域相结合，并共同解除MICAL的酶自动抑制。除了作为上游的MICAL激活因子外，CRMP还在MICAL下游发挥作用，抑制其催化结构域。一种组成型激活的CRMP突变体比野生型CRMP更有效地抑制MICAL活性，这表明CRMP或与CRMP相关的因子是MICAL的底物。因此，复杂的神经毡蛋白/CRMP/MICAL相互作用将信号素信号转导为轴突导向。
Semaphorin activation of Plexin (Plex) receptors provides axonal guidance during neuronal development. Two families of cytoplasmic proteins, collapsin response mediator proteins (CRMPs) and molecules interacting with CasL (MICALs), have been implicated in Plexin function. The relationship between CRMP and MICAL signaling has not been defined nor is the mechanism by which Plexin activates MICAL clear. Here, we show that CRMP and MICAL physically associate and that Sema signaling promotes this association. MICAL enzymatic activity is inhibited by the C-terminal domain of MICAL. CRMP and Plexin associate with nonenzymatic and enzymatic domains of MICAL and together release MICAL enzymatic autoinhibition. In addition to acting as an upstream MICAL activator, CRMP functions downstream of MICAL, inhibiting the catalytic domain. A constitutively active CRMP mutant inhibits MICAL activity more potently than does wild-type CRMP, suggesting that CRMP or a CRMP-associated factor is a MICAL substrate. Thus, complex Plex/CRMP/MICAL interactions transduce Semaphorin signaling into axon guidance.