Grant: Project Grant

Proteins typically need to adopt a specific three-dimensional conformation to gain functionality. Failure to reach or maintain the proper conformation is deleterious, as proteins have then the tendency to aggregate. Therefore, a large number of different protein chaperones has evolved, nearly 200 in humans, in order to support protein folding. However, the capacity to support protein folding diminishes upon aging and under stress conditions, which partially explains why protein deposition is often observed in neurodegenerative diseases such as in Huntington's disease. Despite major efforts, there is still no cure for these diseases, partially due to our limited knowledge of how proteins are folded in the cells. Interestingly, several chaperones can reduce the disease burden and protein aggregation when over-expressed, like DNAJB6 and DNAJB8 that is normally only expressed in testis. Nonetheless, the normal functions of these two related co-chaperones are not well understood. Our preliminary work suggest that these two similar chaperones prevent the aggregation of different sets of proteins (which are also referred as clients). Furthermore, our data indicate that the cell localization of DNAJB6 may greatly influence its function. We will further develop our proteomic approach to better characterize which clients interact with each chaperone, and determine which elements on these chaperones dictate client specificity. Because the nuclear isoform of DNAJB6 prominently interacts with disordered proteins, we will examine whether this isoform is required to prevent aggregation of these proteins. In contrast, the cytosolic isoform of DNAJB6 interacts with a component of the proteasome degradation machinery. Therefore, we will determine whether DNAJB6 is important for the folding of the proteasomal subunit and impact proteasome function. Our work will help elucidate the function of conserved chaperones that have potential major roles in protein homeostasis.