Grant: Project Grant

Gene mutations that cause diseases often do so by causing misfolding and degradation of the mutant proteins. Protein misfolding occurs when a protein does not attain its so-called native structure, which is reached when the protein is properly folded to perform its function in the cell. Our goal is to better understand how mutant proteins that misfold are recognized by elements of the ubiquitin proteasome system. The ubiquitin proteasome system consists of groups of enzymes that first mark proteins targeted for degradation by attaching to them a small protein tag called ubiquitin. These ubiquitin-tagged proteins are then recognized by the proteasome, which eliminates them from the cell. Our main hypothesis is there are several degradation paths for different groups of proteins that misfold due to mutations. To test this idea, we will analyze using different cell-based assays a large panel of mutations that have been associated to genetic disorders or diseases. More specifically, we will focus on missense mutations that induce the change of single amino acids. First, we will identify which mutated cytosolic proteins are degraded by the ubiquitin proteasome system from a large panel of known disease-associated mutations. We will then determine which known elements of the ubiquitin proteasome system target these misfolded mutant proteins. A major question is how E3 enzymes that attach ubiquitin recognize misfolded proteins. To address this question, we will employ the identified mutant proteins as model substrates to better identify which regions or domains on E3 enzymes recognize the misfolded proteins. Finally, we will set up a screen to identify novel genes involved in targeting misfolded proteins for degradation. By better understanding how misfolded proteins are triaged within the cell, we will gain fundamental knowledge of disease mechanisms, leading to potential novel therapeutic approaches.