The Role of Phosphorylation in Modulating Hsp90 Chaperone Activity and its Co-chaperones SGT and Aha1

• Grant number: 24/02293-0
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2024
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Agreement: CNPq
• Principal Investigator: Julio Cesar Borges
• Grantee: Julio Cesar Borges
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• City of the host institution: São Carlos
• Associated research grant: 17/26131-5 - THE CHAPEROME: STUDY OF THE RELATIONSHIP OF THE STRUCTURE OF ITS COMPONENTS AND THE MAINTENANCE OF PROTEOSTASIS, AP.TEM
• Associated research grant(s): 25/13886-4 - Study of the Interaction between Hsp90 and Aha1 in Leishmania braziliensis by Biophysical Approaches, AP.R
• Associated scholarship(s): 24/18726-2 - The role of phosphorylation in modulating the chaperone activity of Hsp90 and its co-chaperones SGT and Aha1, BP.JD

Abstract

This project investigates the regulatory role of phosphorylation in modulating protein-protein interactions and chaperone activity of the Hsp90/SGT and Hsp90/Aha1 complex in Leishmania braziliensis. Hsp90 acts as a molecular chaperone assisting in folding, maturation and stabilization of several client proteins, in addition to integrating and coordinating crucial cell signaling pathways. To exert such functions, Hsp90 interacts with a large number of co-chaperones, including SGT and. Previous studies indicate that the chaperone activity of Hsp90 complexes and their interactions with co-chaperones can be regulated by post-translational modifications such as phosphorylation. However, the mechanisms and functional consequences of this regulation remain obscure. This project will investigate the modulatory role of phosphorylation in Hsp90, SGT and Aha1 through: 1) Mapping phosphorylation sites; 2) Generation of phospho-deficient mutants; 3) Biochemical, structural and functional analyses of these mutants regarding protein interactions, dynamics and chaperone activity. The results will provide new insights into how post-translational signaling integrates and modulates the function of central chaperones and associated protein networks. In addition, they may aid in the planning of new therapies for diseases based on pharmacological manipulation of the protein folding machinery. (AU)