Some (dis)assembly required: partial unfolding in the Par-6 allosteric switch
Name
12551_2015_Article_164.pdf
Size
702.76 KB
Format
Adobe PDF
Checksum (MD5)
0117c8ac6803a6b1279fc684b0ae7c54
Author(s)
Volkman, Brian F.
Whitney, Dustin S
Date Issued
February 2015
Journal
Biophysical Reviews
Publisher
Springer Berlin Heidelberg
Citation
Whitney, Dustin S., and Brian F. Volkman. “Some (dis)assembly Required: Partial Unfolding in the Par-6 Allosteric Switch.” Biophysical Reviews 7, no. 2 (February 7, 2015): 183–190.
Version
Author's final manuscript
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, which 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1007/s12551-015-0164-8
