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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.

Animation: The interplay between APC/C, UBE2S, and UBE2C to ubiquitinate substrates during rapid cell cycle transitions.

In the video the gray blob with eyes is the APC/C. The car speeds along with the three protein complexes that are working together as fast as they can to reach the finish line and complete mitosis. ~Animation by Alejandro R. Martinez Chacin.

Martinez-Chacin RC et al. Ubiquitin chain-elongating enzyme UBE2S activates the RING E3 ligase APC/C for substrate priming. Nat Struct Mol Biol. 2020 Jun;27(6):550-560.