A prevalent form of eukaryotic regulation for countless cellular processes is ubiquitin (Ub)-dependent protein destruction. Defects in the ubiquitination machinery result in a wide range of diseases, including numerous cancers and Alzheimer’s disease. Ubiquitin is conjugated to proteins in the cell by hundreds of enzymes known as ubiquitin ligases. These enzymes can be massive (>1 MDa in size) and dynamic protein complexes. In my lab, we use a hybrid technological approach, including enzyme kinetics, mutagenesis, X-ray crystallography and cryo-EM, to understand the catalytic mechanisms of these behemoth assemblies.

From a therapeutic perspective, ubiquitin ligases can be harnessed for targeted protein degradation. In this approach, ubiquitin ligases are repurposed by PROTACs (Proteolysis targeting chimeras) or molecular glues to degrade disease-causing proteins where traditional small molecule inhibitors are unavailable. These molecules hold tremendous potential for the advancement of precision medicine. My lab works to develop new technologies and identify these molecules through both industry and academic collaborations.