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.
Molecular mechanisms of ubiquitination and phosphorylation
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 (DFG) and the EMBO Young Investigator Programme.
Liess A, Kucerova A, Schweimer K, Yu L, Roumeliotis T, Diebold M, Dybkov O, Sotriffer C, Urlaub H, Choudhary J, Mansfeld J, Lorenz S. Auto-inhibition mechanism of the ubiquitin-conjugating enzyme UBE2S by auto-ubiquitination. Structure; accepted
Ries LK, Sander B, Deol KK, Letzelter MA, Strieter ER, Lorenz S. Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity. J Biol Chem. 2019; 294: 6113-6129
Chen D, Gehringer M, Lorenz S. (2018) Developing small-molecule inhibitors of HECT-type ubiquitin ligases for therapeutic applications: challenges and opportunities. ChemBioChem 2018 Oct 18;19(20):2123-2135.
Lorenz S (2017). Structural mechanisms of HECT-type ubiquitin ligases. Biol Chem 399(2):127-145
Sander B, Xu W, Eilers M, Popov N, Lorenz S (2017). A conformational switch regulates the ubiquitin ligase HUWE1. eLife 2017;6:e21036
Lorenz S, Bhattacharyya M, Feiler C, Rape M, Kuriyan J (2016). Crystal structure of a Ube2S-ubiquitin conjugate. PLoS One 11(2):e0147550
Lorenz S, Deng T, Hantschel O, Superti-Furga G, Kuriyan J (2015). Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity. Biochemical Journal, 468(2):283-91
Lorenz S, Cantor AJ, Rape M, Kuriyan J (2013). Macromolecular juggling by ubiquitylation enzymes BMC Biology 11: 65
Wickliffe KE, Lorenz S*, Wemmer DE, Kuriyan J, Rape M (2011). The mechanism of linkage-specific ubiquitin chain elongation by a single subunit E2. Cell 144(5): 769-781
*shared first and shared corresponding author
Dr. Yahui Liu
Member - Graduate School of Life Sciences (GSLS)
Member - various GSLS thesis committees (biomedicine as well as infection & immunity)
Supervisor - Graduate School of Life Sciences, Biomedicine
The current term program can be found here.