Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition
Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition
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DOI：
10.1016/s1097-2765(04)00086-3
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发表时间：
2004-03-12
期刊：
影响因子：
16
通讯作者：
Prehoda, KE
中科院分区：
文献类型：
--
作者：
Peterson, FC;Penkert, RR;Prehoda, KE
蛋白质相互作用结构域的调节是细胞信号传导动力学所必需的。在这里，我们表明，PDZ蛋白的相互作用域从细胞极性蛋白Par-6是由Rho GTdR Cdc 42。Cdc 42与PDZ结构域相邻的CRIB结构域结合，使Par-6 PDZ对其羧基末端配体的亲和力增加约13倍。Par-6 PDZ调节是功能所需的，因为Cdc 42-Par-6 PDZ偶联的突变破坏导致极化MDCK上皮细胞中Par-6的失活。结构分析表明，自由PDZ结构域有几个偏离典型的PDZ构象，占其低配体亲和力。调控是由CRIB-PDZ模块中Cdc 42诱导的构象转变引起的，该构象转变导致PDZ呈现典型的高亲和力PDZ构象。Par-6的偶联CRIB和PDZ结构揭示了如何将简单的结合结构域组合以产生复杂的调节。
Regulation of protein interaction domains is required for cellular signaling dynamics. Here, we show that the PDZ protein interaction domain from the cell polarity protein Par-6 is regulated by the Rho GTPase Cdc42. Cdc42 binds to a CRIB domain adjacent to the PDZ domain, increasing the affinity of the Par-6 PDZ for its carboxy-terminal ligand by similar to13-fold. Par-6 PDZ regulation is required for function as mutational disruption of Cdc42-Par-6 PDZ coupling leads to inactivation of Par-6 in polarized MDCK epithelial cells. Structural analysis reveals that the free PDZ domain has several deviations from the canonical PDZ conformation that account for its low ligand affinity. Regulation results from a Cdc42-induced conformational transition in the CRIB-PDZ module that causes the PDZ to assume a canonical, high-affinity PDZ conformation. The coupled CRIB and PDZ architecture of Par-6 reveals how simple binding domains can be combined to yield complex regulation.