Hsp70-DNAJ Molecular Interfaces: Effects of Phosphorylation on Structure, Function, and Recognition of Amyloidogenic Proteins

• Grant number: 25/19681-5
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2026
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Carlos Henrique Inacio Ramos
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas

Abstract

Reports of diseases associated with protein misfolding have increased significantly since the discovery that protein aggregates form within cells and can trigger cytotoxicity, as observed in the relationship between ¿-synuclein and Parkinson's disease. Consequently, molecular chaperones and heat shock proteins (HSPs) have emerged as natural candidates for the development of therapeutic strategies. Hsp70 family chaperones assist in protein folding, primarily aided by Hsp40 (DNAJ) cochaperones. Recently, it has been shown that Hsp70/DNAJ/Hsp110 chaperone complexes are involved in aggregate reactivation, with DNAJ proteins playing a selective role in aggregate recognition. In this project, we aim to advance the understanding of the conformational mechanisms and contact regions between DNAJ cochaperones and amyloidogenic proteins. To this end, we will focus on: expressing and purifying human Hsp70 and DNAJ proteins; characterizing their interactions and role in the reactivation of ¿-synuclein amyloids;generating and analyzing phosphomimetic DNAJ mutants to investigate the impact of post-translational modifications on the conformation and function of this cochaperone. Our extensive expertise in protein research, encompassing structure, function, aggregation, and phase transitions, will be fundamental to this study. The results are expected to establish a model for the action of molecular chaperones in regulating ¿-synuclein function and aggregation, offering new perspectives for interventions in amyloidogenic diseases. (AU)