caa a22 4500 606243038 CHVBK 20210128101322.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s12551-015-0164-8 doi (NATIONALLICENCE)springer-10.1007/s12551-015-0164-8 Some (dis)assembly required: partial unfolding in the Par-6 allosteric switch [Elektronische Daten] [Dustin Whitney, Brian Volkman] 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. International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg, 2015 Protein folding nationallicence NMR nationallicence PDZ domain nationallicence Allostery nationallicence Conformational exchange nationallicence Cell polarity nationallicence Whitney Dustin Department of Biochemistry, Medical College of Wiscsonsin, 52336, Milwaukee, WI, USA aut Volkman Brian Department of Biochemistry, Medical College of Wiscsonsin, 52336, Milwaukee, WI, USA aut Biophysical Reviews Springer Berlin Heidelberg 7/2(2015-06-01), 183-190 1867-2450 7:2<183 2015 7 12551 https://doi.org/10.1007/s12551-015-0164-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s12551-015-0164-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Whitney Dustin Department of Biochemistry, Medical College of Wiscsonsin, 52336, Milwaukee, WI, USA aut NATIONALLICENCE 700 1- Volkman Brian Department of Biochemistry, Medical College of Wiscsonsin, 52336, Milwaukee, WI, USA aut NATIONALLICENCE 773 0- Biophysical Reviews Springer Berlin Heidelberg 7/2(2015-06-01), 183-190 1867-2450 7:2<183 2015 7 12551