The role of phosphorylation in modulating the chaperone activity of Hsp90 and its co-chaperones SGT and Aha1

• Grant number: 24/18726-2
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Julio Cesar Borges
• Grantee: Leijiane Figueira de Sousa
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 24/02293-0 - The Role of Phosphorylation in Modulating Hsp90 Chaperone Activity and its Co-chaperones SGT and Aha1, AP.R

Abstract

This project investigates the regulatory role of phosphorylation in modulating protein-protein interactions and chaperone activity of the Hsp90/SGT and Hsp90/Aha1 complexes in Leishmania braziliensis. Hsp90 functions as a molecular chaperone, assisting in the folding, maturation, and stabilization of various client proteins, as well as integrating and coordinating crucial cellular signaling pathways. To perform these functions, Hsp90 interacts with a large number of co-chaperones, including SGT and Aha1. Previous studies indicate that the chaperone activity of the Hsp90 complex and its 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 of 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. Furthermore, they may aid in the design of novel therapies for diseases, based on pharmacological manipulation of the protein folding machinery.