Mechanism of activation of the Formin protein Daam1
Mechanism of activation of the Formin protein Daam1
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DOI：
10.1073/pnas.0707277105
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发表时间：
2008-01-08
影响因子：
11.1
通讯作者：
Habas, Raymond
中科院分区：
文献类型：
--
作者：
Liu, Wei;Sato, Akira;Habas, Raymond
形成蛋白是介导细胞骨架重组的核心参与者，并且上位地位于Rho激活的下游途径中。这些蛋白质以自抑制状态存在于细胞质中，其由氨基末端GT3结合结构域（GBD）（其包括透明抑制结构域（DID））和羧基末端透明自调节结构域（DAD）之间的分子内相互作用介导。已经提出，Rho在GBD内的结合通过破坏DID/DAD相互作用将该分子从自抑制释放。在这里，我们报告说，Daam 1没有显着激活Rho结合，而是通过其与Dishevelled（Dvl）的相互作用。DAD结构域的去除破坏DvI和Daam 1之间的相互作用，DvI与Daam 1的结合破坏GBD和DAD之间介导Daam 1自身抑制的相互作用。DAD内的突变或DAD的去除将Daam 1转化为可以诱导Rho活化的活性蛋白。我们进一步表明，DvI协同Daam 1调节原肠胚在非洲爪蟾胚胎发生和激活Daam 1的表达可以挽救受损的会聚延伸运动失调的非经典Wnt信号。我们的研究共同定义了羧基末端结合伴侣DvI的重要性，DvI导致Daam 1的激活。
The Formin proteins are central players in mediating cytoskeletal reorganization and are epistatically positioned in a pathway downstream of Rho activation. These proteins exist in the cytoplasm in an autoinhibited state, which is mediated by intramolecular interactions between the amino-terminal GTPase binding domain (GBD) that encompasses the diaphanous inhibitory domain (DID) and the carboxyl-terminal diaphanous autoregulatory domain (DAD). It has been proposed that the binding of Rho within the GBD releases this molecule from autoinhibition by disrupting the DID/DAD interactions. Here we report that Daam1 is not significantly activated by Rho binding but rather by its interaction with Dishevelled (Dvl). Removal of the DAD domain disrupts interactions between DvI and Daam1, and the binding of DvI to Daam1 disrupts the interaction between the GBD and DAD that mediates Daam1 autoinhibition. Mutations within or removal of the DAD converts Daam1 into an active protein that can induce Rho activation. We further demonstrate that DvI synergizes with Daam1 to regulate gastrulation during Xenopus embryogenesis and that expression of activated Daam1 can rescue impaired convergent extension movements resulting from deregulated noncanonical Wnt signaling. Our studies together define the importance of a carboxyl-terminal binding partner, DvI, that leads to the activation of Daam1.