Cells need to regulate the abundance, the localization, and the activity of proteins in response to a myriad of stimuli. A major way to accomplish this challenging task is through posttranslational modifications. Research in my lab is directed at understanding the structural basis and functional consequences of posttranslational modifications. In particular, we focus on enzymes of the ubiquitination cascade and protein tyrosine kinases. We follow an interdisciplinary approach by combining X-ray crystallography and NMR spectroscopy with various other biophysical, biochemical, and cell biological techniques.
Ubiquitin is an extremely versatile posttranslational modifier whose diverse biological roles are far from understood on a molecular level. Target proteins may be modified with a single ubiquitin molecule, with multiple individual ubiquitin molecules, or with polymeric ubiquitin chains that can, in turn, have many different topologies. These different types of ubiquitin modifications can trigger distinct physiological responses, such as the proteasomal degradation of target proteins, changes in protein localization, or the reorganization of signaling complexes. Therefore, ubiquitination reactions in the cell ought to be highly specific.
At the University of California, Berkeley, my colleagues and I have uncovered the molecular mechanism of how one specific ubiquitin chain type (Lys11-linked chains) involved in cell cycle regulation is formed. In many other cases, the determinants of linkage specificity and target protein selection remain elusive and are thus the subject of ongoing studies in my lab. We also explore how binding partners affect the structure and conformational dynamics of ubiquitination enzymes to provide an additional layer of regulation. Furthermore, our studies probe the crosstalk of the ubiquitination machinery with other types of posttranslational modifications, such as phosphorylation. Our mechanistic insights into ubiquitination enzymes will ultimately help us to functionally interrogate and manipulate distinct pathways using chemical probes. 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 Pharmaceuticals) in the treatment of multiple myeloma and mantle cell lymphoma, but is largely underexploited to date.
Our research group is supported by the Emmy Noether Program of the German Research Foundation.