The Structural Basis for Cdc42-Induced Dimerization of IQGAPs.
The Structural Basis for Cdc42-Induced Dimerization of IQGAPs.
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DOI：
10.1016/j.str.2016.06.016
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发表时间：
2016-09-06
期刊：
影响因子：
5.7
通讯作者：
Worthylake, David K.
中科院分区：
文献类型：
--
作者：
LeCour, Louis, Jr.;Boyapati, Vamsi. K.;Liu, Jing;Li, Zhigang;Sacks, David B.;Worthylake, David K.
在信号传导中，Rho家族GTP酶结合效应蛋白并改变其行为。在这里，我们展示了与IQGAP 2的GTP酶激活蛋白（GAP）相关结构域（GRD）结合的Cdc 42·GTP的晶体结构。Cdc 42的四个分子与两个GRD分子结合，这两个GRD分子以平行的二聚体彼此结合。两个Cdc 42与Ras/RasGAP相互作用的结合非常相似，而另外两个主要与来自两个GRD的“额外结构域”序列结合-将GRD连接在一起。量热法证实了Cdc 42·GTP与IQGAP 2和IQGAP 1的GRD的双位点结合。重要的额外结构域残基的突变减少了与单一位点的结合，并消除了Cdc 42与更大的IQGAP 1片段的结合。重要的是，Rac 1·GTP仅显示与GRD的单位点结合，表明只有Cdc 42促进IQGAP二聚化。该结构鉴定了Cdc 42在蛋白质二聚化中的意想不到的作用，从而扩展了Ras家族蛋白质与其靶标相互作用的库。eTOC Blurb：三种人类IQGAP是多域支架，影响许多细胞过程，包括神经突生长和致癌作用。常见的结合伴侣包括Cdc 42和Rac 1的活性形式。在这里，LeCour等人表明Cdc 42稳定了IQGAP二聚体，使受体信号下游的二聚体形成受到调节。
In signaling, Rho-family GTPases bind effector proteins and alter their behavior. Here we present the crystal structure of Cdc42•GTP bound to the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP2. Four molecules of Cdc42 are bound to two GRD molecules, which bind each other in a parallel dimer. Two Cdc42s bind very similarly to the Ras/RasGAP interaction, while the other two bind primarily to “extra domain” sequences from both GRDs –tying the GRDs together. Calorimetry confirms two-site binding of Cdc42•GTP for the GRDs of both IQGAP2 and IQGAP1. Mutation of important extra domain residues reduces binding to single-site and abrogates Cdc42 binding to a much larger IQGAP1 fragment. Importantly, Rac1•GTP displays only single-site binding to the GRDs, indicating that just Cdc42 promotes IQGAP dimerization. The structure identifies an unexpected role for Cdc42 in protein dimerization thus expanding the repertoire of interactions of Ras family proteins with their targets. eTOC Blurb: The three human IQGAPs are multi-domain scaffolds affecting many cellular processes including neurite outgrowth and carcinogenesis. Common binding partners include the active forms of Cdc42 and Rac1. Here, LeCour et al. show that Cdc42 stabilizes IQGAP dimers, enabling regulated dimer formation downstream of receptor signaling.
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影响因子：
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作者：
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影响因子：
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作者：
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发表时间：
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期刊：
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影响因子：
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作者：
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