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Mapping contact regions between cochaperones from Hsp40 family and proteins involved in amyloidogenic diseases towards the understanding of the mechanisms for protein aggregates reactivation

Abstract

The reports of diseases related to protein misfolding have increased considerably since the discovery that protein aggregates can be formed in cells and can trigger cytotoxic action. Therefore, molecular chaperones and/or heat shock proteins (HSPs) have become natural candidates in the study of strategies for treatment of these diseases. The chaperones of the Hsp70 family are involved in the assistance of protein folding, being assisted mainly by cochaperones of the HSP40 family (DNAJ), which are divided into subclasses A and B that recognize and transfer partially folded proteins to Hsp70. Recently, it was shown that in humans, chaperone complexes formed by Hsp70/DNAJB/Hsp110 are involved in aggregate reactivation, where proteins of the DNAJB subclass have a selective role in recognizing different aggregates. In this project we propose a further investigation, aiming to understand the conformational mechanisms and the contact regions between human cochaperones from DNAJB family and proteins involved in amyloidogenic diseases. To this end we propose: 1) To express and purify at least two human DNAJB; 2) To express mutants to scrutinize the role of amino and carboxy-terminal regions in the process of interaction to HSP70 and dimerization, respectively; 3)To characterize the protection and reactivation of alpha-synuclein by DNAJB; 4)To assign at least one human DNAJB by NMR, using data obtained for the yeast homologue; 5)To express phosphomimetic mutants to understand the role of post-translational modifications in DNAJB function. The results obtained have a high potential to contribute to the understanding of the mechanisms of reactivation of protein aggregates. (AU)

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