Allosteric Activation of the Par-6 PDZ via a Partial Unfolding Transition

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• 作者：Dustin S. Whitney ; Francis C. Peterson ; Evgenii L. Kovrigin ; Brian F. Volkman
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：June 26, 2013
• 年：2013
• 卷：135
• 期：25
• 页码：9377-9383
• 全文大小：410K
• 年卷期：v.135,no.25(June 26, 2013)
• ISSN：1520-5126

文摘

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.