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Abstract
Par-6 is a scaffold protein that organizes other proteins into a complex required
to initiate and maintain cell polarity. Cdc42-GTP binds the CRIB module of Par-6 and
alters the binding affinity of the adjoining PDZ domain. Allosteric regulation of
the Par-6 PDZ domain was first demonstrated using a peptide identified in a screen
of typical carboxyl-terminal ligands. Crumbs, a membrane protein that localizes a
conserved polarity complex, was subsequently identified as a functional partner for
Par-6 that likely interacts with the PDZ domain. Here we show by nuclear magnetic
resonance that Par-6 binds a Crumbs carboxyl-terminal peptide and report the crystal
structure of the PDZ-peptide complex. The Crumbs peptide binds Par-6 more tightly
than the previously studied carboxyl peptide ligand and interacts with the CRIB-PDZ
module in a Cdc42-dependent manner. The Crumbs:Par-6 crystal structure reveals specific
PDZ-peptide contacts that contribute to its higher affinity and Cdc42-enhanced binding.
Comparisons with existing structures suggest that multiple C-terminal Par-6 ligands
respond to a common conformational switch that transmits the allosteric effects of
GTPase binding.