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Publication Abstract from PubMed

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.

Binding of Crumbs to the Par-6 CRIB-PDZ Module Is Regulated by Cdc42.,Whitney DS, Peterson FC, Kittell AW, Egner JM, Prehoda KE, Volkman BF Biochemistry. 2016 Mar 15;55(10):1455-61. doi: 10.1021/acs.biochem.5b01342. Epub , 2016 Mar 3. PMID:26894406^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.