Structural and mechanistic insights into the interaction between Rho and mammalian Dia
Structural and mechanistic insights into the interaction between Rho and mammalian Dia
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DOI：
10.1038/nature03604
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发表时间：
2005-05-26
期刊：
影响因子：
64.8
通讯作者：
Wittinghofer, A
中科院分区：
文献类型：
--
作者：
Rose, R;Weyand, M;Wittinghofer, A
Formins参与了各种需要细胞骨架重塑的细胞过程。它们含有福尔曼同源结构域FH1和FH2，它们启动肌动蛋白组装(1，2)。透明相关的福梅素形成一个亚基，其特征是氨基末端的Rho GTP酶结合结构域(GBD)和FH3结构域，以某种方式与羧基末端的透明自调节结构域(DAD)结合，以保持蛋白质的非活性构象(3，4)。当激活的Rho蛋白结合时，DAD被释放，并诱导Forin成核和拉长未分支的肌动蛋白细丝的能力。在这里，我们介绍了RhoC的晶体结构，它与哺乳动物透明蛋白1(MDia1)的调控N端(MDia1)含有GBD/FH3区，这是一种带有Aradillo重复序列的全螺旋结构。RHO使用它的“开关”区域与GBD/FH3的两个亚域相互作用。我们发现mDia1的FH3结构域形成了一个稳定的二聚体，并鉴定了DAD结合部位。虽然Rho和DAD在mDia1的N端片段上的结合是互斥的，但它们的结合部位只有部分重叠。基于我们的结果，我们提出了一个Rho和DAD对mDia1调控的结构模型。
Formins are involved in a variety of cellular processes that require the remodelling of the cytoskeleton. They contain formin homology domains FH1 and FH2, which initiate actin assembly(1,2). The Diaphanous-related formins form a subgroup that is characterized by an amino-terminal Rho GTPase-binding domain (GBD) and an FH3 domain, which bind somehow to the carboxy-terminal Diaphanous autoregulatory domain ( DAD) to keep the protein in an inactive conformation(3,4). Upon binding of activated Rho proteins, the DAD is released and the ability of the formin to nucleate and elongate unbranched actin filaments is induced. Here we present the crystal structure of RhoC in complex with the regulatory N terminus of mammalian Diaphanous 1 (mDia1) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with two subdomains of GBD/FH3. We show that the FH3 domain of mDia1 forms a stable dimer and we also identify the DAD-binding site. Although binding of Rho and DAD on the N-terminal fragment of mDia1 are mutually exclusive, their binding sites are only partially overlapping. On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD.