Correlation between metals and protein homeostasis: initial studies investigating the incorporation of the 68Zn isotope into the Hsp40 co-chaperone and its effect on yeast

• Grant number: 18/00768-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2018
• End date: December 01, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Jemmyson Romário de Jesus
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The last decades have seen an rise in the number of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, mainly due to the general increase in life expectancy. In the United States, which maintains up-to-date statistics, it is estimated that one third of the elderlies are dying from Alzheimer's. As a matter of fact, Alzheimer's has became the sixth most common cause of mortality. Neurodegenerative diseases are related to incorrect folding and aggregation of specific proteins. Interestingly, recent studies have shown that micronutrients, mainly zinc, appear to protect against aggregation and their supplementation appears to decrease the symptoms of these diseases. Our research group aims to understand the cellular chaperoma, which involves chaperonas and heat shock proteins (Hsps), which aid protein folding, protect against aggregation and can resolubilize and re-establish aggregates already formed. The beneficial role of the chaperoma on these diseases has already been demonstrated in several studies, although knowledge about the mechanism of action is still only initial. Fascinating, some components of the chaperoma are also involved with the homeostasis of metals in the cell and therefore could also act on this front in relation to the fight of diseases caused by correct folding. Therefore, this project proposes the characterization of the binding of metals, initially zinc, in some chaperones, mainly Hsp40, which has a zinc-finger domain. The first investigative strategy consists of incorporating the 68Zn isotope into the recombinant Hsp40 by means of an enrichment experiment in order to evaluate the effects of this incorporation into the conformation and the function of the chaperone. As a control, a mutant, in which the 'zinc-finger' domain is deleted, will be used. In parallel, we will investigate the uptake of 68Zn into both a wild-type Saccharomyces cerevisiae yeast and a strain deleted from the Hsp40 gene. Another control will consist of complementing the knocked-out yeast with the mutant Hsp40 gene. In addition to the effect on yeast growth, the protein expression and the pattern of aggregate formation in the cell will be evaluated. The expected results will be used to propose a mechanism involving zinc and protein aggregation, hopefully suggesting the basis for studies involving other metals and potential interaction with the human chaperoma. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE JESUS, JEMMYSON ROMARIO; GUIMARAES, IVANILCE CRISTINA; ZEZZI ARRUDA, MARCO AURELIO. Quantifying proteins at microgram levels integrating gel electrophoresis and smartphone technology. JOURNAL OF PROTEOMICS, v. 198, p. 45-49, APR 30 2019. (16/07384-7, 18/00768-0)

DE JESUS, JEMMYSON ROMARIO; BARBOSA ARAGAO, ANNELIZE ZAMBON; ZEZZI ARRUDA, MARCO AURELIO; RAMOS, CARLOS H., I. Optimization of a Methodology for Quantification and Removal of Zinc Gives Insights Into the Effect of This Metal on the Stability and Function of the Zinc-Binding Co-chaperone Ydj1. RONTIERS IN CHEMISTR, v. 7, p. 10-pg., 2019-06-11. (17/26131-5, 12/50161-8, 18/00768-0)

DE JESUS, JEMMYSON ROMARIO; BARBOSA ARAGAO, ANNELIZE ZAMBON; ZEZZI ARRUDA, MARCO AURELIO; RAMOS, I, CARLOS H.. Optimization of a Methodology for Quantification and Removal of Zinc Gives Insights Into the Effect of This Metal on the Stability and Function of the Zinc-Binding Co-chaperone Ydj1. FRONTIERS IN CHEMISTRY, v. 7, JUN 11 2019. (17/26131-5, 12/50161-8, 18/00768-0)

DE JESUS, JEMMYSON R.; LINHARES, LEONARDO A.; ARAGA, ANNELIZE Z. B.; ARRUDA, MARCO A. Z.; RAMOS, CARLOS H. I.. The stability and function of human cochaperone Hsp40/DNAJA1 are affected by zinc removal and partially restored by copper. Biochimie, v. 213, p. 7-pg., 2023-05-30. (17/26131-5, 19/24445-8, 14/50867-3, 18/00768-0, 18/25207-0, 20/08543-7)