Journal
BIOCHEMISTRY
Volume 55, Issue 10, Pages 1455-1461Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.5b01342
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Funding
- U.S. Department of Health and Human Services, National Institutes of Health Grants [GM068032RO1, AI058072]
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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.
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