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Using calorimetric techniques to characterize protein-protein interactions: applications in molecular chaperones

Grant number: 11/22212-4
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): April 01, 2012
Effective date (End): July 31, 2012
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Carlos Henrique Inacio Ramos
Grantee:Leticia Maria Zanphorlin
Supervisor: Conceição A. S. A. Minetti
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Rutgers The State University of New Jersey, New Brunswick, United States  
Associated to the scholarship:10/05417-9 - Investigation of the effect of polyphenols on the mechanism of amyloid fibril formation., BP.DR


Molecular chaperones, also described as heat shock proteins (Heat shock protein, Hsp) act preventing aggregation and incorrect folding of proteins. The incorrect protein folding causes loss of function, leading to diseases like Alzheimer's and Parkinson's disease and some cancers with subsequent decrease in life expectancy. The Hsp90 molecular chaperone is one of the most important, considered essential for cell viability in eukaryotes and is usually associated with proteins acting in the cycle and cell signaling. Moreover, recently it was implicated in the stabilization of the tumor phenotype of various cancers. The interaction with co-chaperones, considered auxiliary proteins of chaperones, enables that Hsp90 acts as a hub protein being a central point of regulation of several proteins and consequently of regulatory pathways. Many of the co-chaperones have one or more TPR domains that interact with the C-terminus of Hsp90. Recent results from our group show the mapping of amino acid residues involved in the interaction between the C-terminal domain of Hsp90 (Hsp90-C) and Tom70 TPR domain using the technique of cross-linking coupled with LC-MS/MS. Thus, the goal in this project is to use calorimetric techniques to characterize the thermodynamic interaction between these proteins based on our previous result. We expect with this, contribute to define the parameters of interaction and generate knowledge at the molecular level that allows the creation of strategies for intervention in the functioning of Hsp90, a target protein in the treatment of cancer. In addition, the client protein of Hsp90, p53, a tumor suppressor protein can, under specific conditions, aggregate and form amyloid fibrils. Aggregation experiments performed in our laboratory showed that Hsp90 was able to inhibit the aggregation of WT and p53 mutant R248Q. Therefore, this work also intend to investigate thermodynamic characteristics of the interaction between p53 (and mutant) and Hsp90. (AU)

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