The attachment of ubiquitin to target proteins regulates a wide range of physiological processes, such as the cell cycle, apoptosis, DNA repair, and receptor signaling. These diverse functions originate, at least in part, from the diverse ways by which ubiquitin can be attached to target proteins. Target proteins may be tagged with one or several individual ubiquitin molecules. Alternatively, the resulting conjugates may undergo further rounds of modification leading to polymeric ubiquitin chains. These chains are linked through isopeptide bonds between the C-terminus of one ubiquitin molecule and a primary amino group on the next molecule. Ubiquitin contains seven lysine residues and a free amino-terminus, so the chains can have many different topologies and, therefore, different functions.


The ubiquitination machinery thus needs to be highly specific in the selection of target proteins, in the selection of ubiquitination sites on these target proteins, and in the formation of isopeptide linkages.  Our lab in interested in uncovering the chemical and structural mechanisms encoding these various layers of specificity. Our studies will not only allow us to understand the various physiological functions of ubiquitin, but also to ultimately manipulate distinct pathways using drugs. The potential of harnessing the ubiquitin system for therapeutic benefit has been widely recognized due to the clinical effectiveness of the proteasome inhibitor Bortezomib / Velcade (Millennium /Takeda) in the treatment of multiple myeloma and mantle cell lymphoma.