Peterson Francis C, Penkert Rhiannon R, Volkman Brian F, Prehoda Kenneth E
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA.
Mol Cell. 2004 Mar 12;13(5):665-76. doi: 10.1016/s1097-2765(04)00086-3.
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 approximately 13-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.
细胞信号转导动力学需要对蛋白质相互作用结构域进行调控。在此，我们表明细胞极性蛋白Par-6的PDZ蛋白相互作用结构域受Rho GTP酶Cdc42的调控。Cdc42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的调控对其功能是必需的，因为Cdc42-Par-6 PDZ偶联的突变破坏会导致极化的MDCK上皮细胞中Par-6失活。结构分析表明，游离的PDZ结构域与典型的PDZ构象有几个偏差，这解释了其低配体亲和力。调控源于CRIB-PDZ模块中Cdc42诱导的构象转变，该转变使PDZ呈现典型的高亲和力PDZ构象。Par-6的CRIB和PDZ耦合结构揭示了简单的结合结构域如何组合以产生复杂的调控。
