Medical College of Wisconsin
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Some (dis)assembly required: partial unfolding in the Par-6 allosteric switch. Biophys Rev 2015 Jun 01;7(2):183-190

Date

08/04/2015

Pubmed ID

26236405

Pubmed Central ID

PMC4519835

DOI

10.1007/s12551-015-0164-8

Abstract

Allostery is commonly described as a functional connection between two distant sites in a protein, where a binding event at one site alters affinity at the other. Here we review the conformational dynamics that encode an allosteric switch in the PDZ domain of Par-6. Par-6 is a scaffold protein that organizes other proteins into a complex required to initiate and maintain cell polarity. NMR measurements revealed that the PDZ domain samples an evolutionarily conserved unfolding intermediate allowing rearrangement of two adjacent loop residues that control ligand binding affinity. Cdc42 binding to Par-6 creates a novel interface between the PDZ domain and the adjoining CRIB motif that stabilizes the high-affinity PDZ conformation. Thermodynamic and kinetic studies suggest that partial PDZ unfolding is an integral part of the Par-6 switching mechanism. The Par-6 CRIB-PDZ module illustrates two important structural aspects of protein evolution: the interface between adjacent domains in the same protein can give rise to allosteric regulation, and thermodynamic stability may be sacrificed to increase the sampling frequency of an unfolding intermediate required for conformational switching.

Author List

Whitney DS, Volkman BF

Author

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




jenkins-FCD Prod-461 7d7c6113fc1a2757d2947d29fae5861c878125ab