Eric Strieter

The overarching goal of my research program is to understand, on a molecular level, how the small protein ubiquitin controls the dynamics of biochemical pathways to maintain normal cellular function. Ubiquitin (Ub) is covalently tethered to proteins through the action of several enzymes. This process is termed ubiquitination and is one of the most prevalent and complex in all eukaryotic organisms. The complexity of protein ubiquitination arises from the ability of Ub to serve as a substrate for subsequent enzymatic transformations that can lead to polymeric Ub chains, which come in diverse sizes and shapes (e.g., linear or branched). The prevailing view is that the diversity of Ub chain types can fine-tune the dynamics of vital cellular processes such as growth, division, DNA repair, and protein degradation. The question that remains unanswered is how different Ub chains regulate distinct biological processes. To address this key issue, we focus on the enzymes that remove Ub modifications: the deubiquitinases or DUBs. Understanding which Ub chain type is targeted for cleavage by each DUB can reveal the critical link between Ub chain type and cellular pathway. Also unknown is the mechanism by which DUBs catalyze the removal of Ub modifications. Addressing this issue is important, as DUBs are important therapeutic targets, and methods to regulate their activity will emerge from an understanding of DUB molecular mechanisms.