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The Schulman lab studies the structural basis for post-translational modification by ubiquitin and ubiquitin-like proteins (Ubls). Post-translational covalent attachment of Ubls to protein targets is a primary eukaryotic regulatory mechanism. There are more than a dozen Ubls in higher eukaryotes—such as ubiquitin, NEDD8, ISG15, and SUMO—that covalently modify myriad substrates. The best understood function of a Ubl modification is ubiquitin-mediated proteasomal degradation. However, different Ubls alter the functions of their targets in different ways, such as by changing the target's subcellular localization, enzymatic activity, or interactions with other proteins or DNA. Moreover, defects in these pathways have been widely associated with diseases such as cancer, neurodegenerative disorders and viral infections.
Ubls are attached to protein targets by a series of molecular handoffs involving an E1 activating enzyme, an E2 conjugating enzyme (or Ubc), an E3 ligase, and the target. First, at the apex of each Ubl's cascade, a dedicated E1 enzyme selects its Ubl and catalyzes adenylation of the Ubl’s C-terminus. The E1 then forms a thioester intermediate between the E1's catalytic cysteine and the Ubl's C terminus, and ultimately catalyzes Ubl transfer to an E2's catalytic cysteine to generate a thioester-linked E2~Ubl covalent product. The E2~Ubl complex typically associates with an E3, which facilitates transfer of the Ubl to the target.
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. Toward this end, the goals of our research are (1) to understand the basic enzymatic mechanisms underlying Ubl attachment to targets, (2) to understand how Ubls are attached selectively, and (3) to understand mechanisms by which Ubl covalent attachment can change enzyme and target function.