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Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90–Client Interactions |
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| Authors: | Dr Antonella Paladino Dr Mark R Woodford Dr Sarah J Backe Dr Rebecca A Sager Dr Priyanka Kancherla Dr Michael A Daneshvar Dr Victor Z Chen Dimitra Bourboulia Dr Elham F Ahanin Dr Chrisostomos Prodromou Dr Greta Bergamaschi Dr Alessandro Strada Dr Marina Cretich Dr Alessandro Gori Dr Marina Veronesi Dr Tiziano Bandiera Renzo Vanna Dr Gennady Bratslavsky Stefano A Serapian Dr Mehdi Mollapour Prof?Dr Giorgio Colombo |
| Institution: | 1. SCITEC-CNR, via Mario Bianco 9, 20131 Milano, Italy
These authors contributed equally to this work.;2. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210 USA These authors contributed equally to this work.;3. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210 USA;4. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210 USA College of Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210 USA;5. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210 USA;6. Genome Damage and Stability Centre, University of Sussex, Brighton, BN1 9RQ UK;7. SCITEC-CNR, via Mario Bianco 9, 20131 Milano, Italy;8. D3-PharmaChemistry, Istituto Italiano di Tecnologia (IIT), Genova, Italy;9. Institute for Photonics and Nanotechnologies, IFN-CNR, c/o Dept. of Physics, Politecnico di Milano, Piazza L. Da Vinci 32, 20133 Milano, Italy;10. University of Pavia, Department of Chemistry, Viale Taramelli 10, 27100 Pavia, Italy;11. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210 USA |
| Abstract: | Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein–protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation. |
| Keywords: | co-chaperones heat shock protein Hsp90 molecular recognition protein dynamics protein–protein interaction inhibitors |