Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition.
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.
Peterson
Francis C
FC
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA.
Penkert
Rhiannon R
RR
Volkman
Brian F
BF
Prehoda
Kenneth E
KE
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology*; D018360:Crystallography, X-Ray; D004285:Dogs; D004330:Drosophila; D004847:Epithelial Cells / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
D011506:Proteins; D020764:cdc42 GTP-Binding Protein