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Allosteric activation of the Par-6 PDZ via a partial unfolding transition. J Am Chem Soc 2013 Jun 26;135(25):9377-83

Date

05/28/2013

Pubmed ID

23705660

Pubmed Central ID

PMC3736553

DOI

10.1021/ja400092a

Scopus ID

2-s2.0-84879539055   6 Citations

Abstract

Proteins exist in a delicate balance between the native and unfolded states, where thermodynamic stability may be sacrificed to attain the flexibility required for efficient catalysis, binding, or allosteric control. Partition-defective 6 (Par-6) regulates the Par polarity complex by transmitting a GTPase signal through the Cdc42/Rac interaction binding PSD-95/Dlg/ZO-1 (CRIB-PDZ) module that alters PDZ ligand binding. Allosteric activation of the PDZ is achieved by local rearrangement of the L164 and K165 side chains to stabilize the interdomain CRIB:PDZ interface and reposition a conserved element of the ligand binding pocket. However, microsecond to millisecond dynamics measurements revealed that L164/K165 exchange requires a larger rearrangement than expected. The margin of thermodynamic stability for the PDZ domain is modest (∼3 kcal/mol) and further reduced by transient interactions with the disordered CRIB domain. Measurements of local structural stability revealed that tertiary contacts within the PDZ are disrupted by a partial unfolding transition that enables interconversion of the L/K switch. The unexpected participation of partial PDZ unfolding in the allosteric mechanism of Par-6 suggests that native-state unfolding may be essential for the function of other marginally stable proteins.

Author List

Whitney DS, Peterson FC, Kovrigin EL, 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
Drosophila Proteins
PDZ Domains
Protein Kinase C
Protein Unfolding
Thermodynamics
jenkins-FCD Prod-461 7d7c6113fc1a2757d2947d29fae5861c878125ab