Post-translational modification by ubiquitin and ubiquitin-like proteins (ubls) is a predominant cellular regulatory mechanism. There are over a dozen ubls in higher eukaryotes, such as ubiquitin, NEDD8, ISG15, and SUMO-1, which covalently modify myriad substrates. The best understood function of a ubl modification is ubiquitin-mediated proteasomal degradation. However, ubiquitin can be attached to proteins in different ways, and the different types of modification by ubiquitin have different functions. As an example, monoubiquitin can serve as a sorting signal to direct proteins to the correct membrane compartment. In addition, different ubls also alter the functions of their targets, for example by changing the target’s enzymatic activity, subcellular localization, or intermolecular interactions.

Our research is devoted to elucidating the detailed molecular basis underlying the conjugation of ubiquitin and ubls to their targets. Our goal is to deduce the rules of catalysis and selectivity of ubl conjugation. The different ubls are conjugated to their targets by parallel but distinct cascades of enzymes, which sequentially involve an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase. In order to understand how a given ubl is coordinated with its particular targets, my laboratory is studying the structures of E1s, E2s, E3s, and their complexes with each other, with their ubl partners, and with their targets. We believe that determining the mechanisms by which enzymes transfer ubls will be of broad importance, much like studies of protein kinases have influenced our knowledge of signaling pathways and their roles in diseases. Indeed, the post-translational modifications by ubiquitin and ubls control a vast array of biological processes including the cell cycle, development, inflammation and the immune response. Moreover, defects in these pathways have been widely associated with diseases such as cancer, neurodegenerative disorders and viral infections.