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Molecular recognition via coupled folding and binding in a TPR domain
Matthew J Cliff1, Mark A Williams, John Brooke-Smith
1Department of Biochemistry and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
Journal of Molecular Biology
|February 17, 2005
Summary
Tetratricopeptide repeat (TPR) domains, crucial for intracellular signaling, are often unfolded at physiological temperatures. Protein binding, like Hsp90 to PP5, induces a stabilized structure through a coupled folding-binding mechanism.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Tetratricopeptide repeat (TPR) domains are protein-protein interaction modules involved in intracellular signaling.
- The TPR domain of protein phosphatase 5 (PP5) interacts with the C-terminus of Hsp90, a key chaperone protein.
Purpose of the Study:
- To investigate the structural dynamics of the PP5 TPR domain at physiological temperatures.
- To elucidate the mechanism of interaction between the PP5 TPR domain and Hsp90.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Circular Dichroism (CD) spectroscopy
- Isothermal Titration Calorimetry (ITC)
Main Results:
- The PP5 TPR domain is largely unfolded at physiological temperatures.
- Binding to an Hsp90-derived pentapeptide (MEEVD) stabilizes a folded structure.
- Thermodynamic analysis revealed a coupled folding-binding mechanism with minimal net effect on affinity across temperatures.
Conclusions:
- The interaction between PP5 TPR and Hsp90 involves a coupled folding-binding mechanism.
- This mechanism, where folding is induced by binding, may be prevalent in other TPR domains.