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A conformational switch in the CRIB-PDZ module of Par-6. Structure 2011 Nov 09;19(11):1711-22 PMID: 22078569 PMCID: PMC3217198

Abstract

Here, we report a novel mechanism of PDZ (PSD-95/Dlg/ZO-1) domain regulation that distortsĀ a conserved element of PDZ ligand recognition. The polarity regulator Par-6 assembles a conserved multiprotein complex and is directly modulated by theĀ 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.

Author List

Whitney DS, Peterson FC, Volkman BF

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Amino Acid Motifs
Animals
Binding Sites
Conserved Sequence
Drosophila Proteins
Drosophila melanogaster
Magnetic Resonance Spectroscopy
Models, Molecular
PDZ Domains
Protein Binding
Protein Kinase C



View this publication's entry at the Pubmed website PMID: 22078569
jenkins-FCD Prod-158 788e756cee95f97989f23472575fc754037544be