Characterization of posttranslational modifications that modulate DNAJB1, a targeting factor of the human Hsp70-based protein disaggregase

• Grant number: 22/03729-0
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2022
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Agreement: Monash University
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Carlos Henrique Inacio Ramos
• Principal researcher abroad: Nadinath B Nillegoda
• Institution abroad: Monash University, Australia
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• 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 scholarship(s): 25/01634-0 - Production of proteins for structure-function relationship studies., BP.TT; 23/06727-1 - Technical assistance to the FAPESP-MONASH Cooperation Project, BP.TT

Abstract

Amyloid-type protein aggregation is a common feature of many neuro/neuromuscular degenerative disorders such as Huntington's disease (HD). Although these diseases show distinct clinical features, at the molecular level, protein aggregation modulates disease progression by a gain-of-toxicity mechanism(s). Recent epidemiological studies by the World Health Organization revealed that >55 million people worldwide are living with such conditions. DNAJB1 targeting factor-containing Hsp70-based protein disaggregases in humans were recently shown to efficiently disassemble amyloid-type aggregates and counteract the associated toxicities, thus showcasing the immense therapeutic value of boosting this activity in cells. The proposed project presents an innovative research program to establish how posttranslational modifications (PTMs) regulate DNAJB1 in amyloid disaggregation function. (AU)