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Oxidative modifications of protein disulfide isomerase and implications to proteopathies

Grant number: 18/01952-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2018
Effective date (End): September 30, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Ohara Augusto
Grantee:Bruna Gutierrez de Souza
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

The protein disulfide isomerase (PDI) is a disulfide / dithiol oxidoreductase that has several essential physiological roles, including the correct folding of newly expressed proteins. It has been shown that PDI content is increased in cellular and animal models of diseases associated with protein aggregation, such as neurodegenerative diseases, and the enzyme has been considered a protection against such diseases. However, PDI has been found in protein inclusions of neurodegenerative diseases, suggesting that post-translational oxidative modifications of the recruited PDI critically affect its activity and anti-aggregation effects. Although proteomic studies have detected oxidative PDI modifications in various animal models and in patients of diseases associated with oxidative stress, little is known about the kinetics and products of PDI oxidation by biological oxidants. But such knowledge is essential to determine which oxidants may have PDI as a relevant biological target, and how such oxidants modify the enzyme to render it dysfunctional and/or aggregated. In this project we will continue previous studies examining the effect of CO2 on the oxidation of PDI by hydrogen peroxide and peroxynitrite. We hope to contribute to the understanding of oxidative modifications that cause protein aggregation and their consequences in proteinopathies. The project is part of CEPID Redoxoma's goals 1 (Biomolecule oxidation and function) and 2 (Thiol-based redox proteins).