Allosteric activation of the Par-6 PDZ via a partial unfolding transition
| Autor: | Brian F. Volkman, Evgenii L. Kovrigin, Francis C. Peterson, Dustin S. Whitney |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Polarity (international relations)
Chemistry PDZ domain Allosteric regulation PDZ Domains General Chemistry CDC42 GTPase Biochemistry Catalysis Article Crystallography Colloid and Surface Chemistry Allosteric Regulation Unfolded protein response Side chain Biophysics Drosophila Proteins Thermodynamics Chemical stability Protein Kinase C Protein Unfolding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|