Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation / physiology
  • Animals
  • Cell Line
  • Cell Polarity / physiology*
  • Crystallography, X-Ray
  • Dogs
  • Drosophila
  • Epithelial Cells / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding / physiology
  • Protein Conformation
  • Protein Structure, Tertiary / physiology
  • Proteins / chemistry
  • Proteins / metabolism*
  • cdc42 GTP-Binding Protein / chemistry
  • cdc42 GTP-Binding Protein / metabolism*


  • Proteins
  • cdc42 GTP-Binding Protein

Associated data

  • PDB/1RY4
  • PDB/1RZX