Biophysical Insights of Hsp40’s interaction with alpha-synuclein

Reports of diseases associated with protein misfolding have increased considerably following the discoveries that protein aggregates can form within cells and may trigger cytotoxicity. Protein aggregates can be considered as a non-functional assembly of one or more proteins, and these aggregates can adopt different conformations, ranging from highly disordered states to near-native and structured amyloid forms. Therefore, molecular chaperones have become natural candidates in the study of therapeutic strategies for these diseases, due to their important role in maintaining protein homeostasis. Chaperones from the Hsp70 family (Heat Shock Protein) are involved in assisting protein folding, and they are primarily supported by co-chaperones of the Hsp40 (DNAJ) family, which are divided into subclasses A, B, and C. Subclasses A and B are known to recognize and transfer partially unfolded proteins to Hsp70. Recently, it was shown that, in humans, chaperone complexes composed of Hsp70/DNAJB/Hsp110 are involved in the reactivation of protein aggregates, where DNAJB subclass proteins appear to play a selective role in recognizing different types of aggregates. In this work, we further investigated this process, aiming to understand the conformational mechanisms and contact regions between a human co-chaperone from the DNAJB family and alpha-synuclein.