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Here, we report a novel mechanism of PDZ (PSD-95/Dlg/ZO-1) domain regulation that distorts a conserved element of PDZ ligand recognition. The polarity regulator Par-6 assembles a conserved multiprotein complex and is directly modulated by the Rho GTPase Cdc42. Cdc42 binds the adjacent Cdc42/Rac interactive binding (CRIB) and PDZ domains of Par-6, increasing C-terminal ligand binding affinity by 10-fold. By solving structures of the isolated PDZ domain and a disulfide-stabilized CRIB-PDZ, we detected a conformational switch that controls affinity by altering the configuration of the conserved "GLGF" loop. As a result, lysine 165 is displaced from the PDZ core by an adjacent hydrophobic residue, disrupting coordination of the PDZ ligand-binding cleft. Stabilization of the CRIB:PDZ interface restores K165 to its canonical location in the binding pocket. We conclude that a unique "dipeptide switch" in the Par-6 PDZ transmits a signal for allosteric activation to the ligand-binding pocket.
A Conformational Switch in the CRIB-PDZ Module of Par-6.,Whitney DS, Peterson FC, Volkman BF Structure. 2011 Nov 9;19(11):1711-22. PMID:22078569[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Whitney DS, Peterson FC, Volkman BF. A Conformational Switch in the CRIB-PDZ Module of Par-6. Structure. 2011 Nov 9;19(11):1711-22. PMID:22078569 doi:10.1016/j.str.2011.07.018
