Ubiquitylation is a reversible post-translational modification that covalently links ubiquitin onto the lysine side chain of a target protein. Classical Lys48-linked polyubiquitylation directs protein degradation through the proteasome pathway, whereas other linkages induce changes in protein localization and activity. Ubiquitin is first loaded by an E1 ubiquitin-activating enzyme onto an E2-ubiquitin-conjugating enzyme. E3 ubiquitin ligases subsequently recruit the charged E2 as well as substrate to catalyze ubiquitin transfer. Over 600 human E3 ligases are identified, offering a rich variety of structures to accommodate substrates of varying shapes and sizes.
Dysregulation of the ubiquitylation process has been linked to many human diseases including cancer, diabetes, hypertension, and neurological diseases such as autism and Parkinson’s disease. The ubiquitin-proteasome system is therefore an attractive area for drug design, as demonstrated by the approval of the proteasome inhibitor Bortezomib for the treatment of myeloma. To advance this work, the SGC aims to understand the structure, function and mechanism of enzymes in the ubiquitylation pathway, with particular emphasis on the Cullin-RING and HECT E3 ligases as well as deubiquitinases (DUBs). We also collaborate extensively to identify novel inhibitors that will alter the activity of such disease-related ligases and proteases.