Study of the molecular chaperone Hsp90 modulation through the characterization of interactions with co-chaperones, client protein, ligands and post-translational modifications

• Grant number: 11/18611-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2011
• End date: January 31, 2013
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Lisandra Marques Gava Borges
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The biological function of proteins is related to its three dimensional structure acquired via protein folding process. In this context, the molecular chaperones play a key role acting as auxiliary protein on protein folding, refolding and dissociation of protein aggregates. Hsp90 is one of the most important molecular chaperones, is essential for cell viability in eukaryotes and is usually associated with proteins involved in cell cycling and cell signaling, which makes these chaperone a very interesting targeting for therapeutic approaches for several diseases. The chaperone activity of Hsp90 can be modulated by other proteins, called co-chaperones, client proteins, ligand interaction and post-translational modifications. Thus, the study of modulators of Hsp90 can help to elucidate major open questions about the function and regulation of Hsp90. The scope of this project is to investigate some co-chaperones and client proteins of Hsp90, involved in cell cycle and transcriptional regulation/chromatin remodeling, for example, the co-chaperone p23 and its variants, the co-chaperones Pih1 and Tah1 and protein clients as Wee1 and CDKs; and how these proteins can act as modulators of Hsp90 function, in addition to study of interaction with ligands such as curcumin a epigallocatechin gallate and characterization of post-translational modifications. The techniques applied for initial characterization are circular dichroism and fluorescence, for further characterization hydrodynamic methods, as dynamic light scattering, SEC-MALS and analytical ultracentrifugation will be utilized. Calorimetric methods as differential scanning calorimetry and isothermal titration calorimetry will be also used; and also the small-angle X-ray scattering technique. In this way, we intend to enhance our understanding of Hsp90 modulation.