Ubiquitin Signaling Specificity
The complexity of biological systems relies on the dynamic formation and reorganization of specific macromolecular complexes. How the underlying interactions are regulated precisely in space and time and deregulated in disease is incompletely understood. It is clear, however, that posttranslational modifications provide critical control circuits for the dynamics of protein complexes and associated functions.
We aim to understand the molecular machinery that drives posttranslational modifications at a structural and functional level and establish paradigms for its specificity. In particular, we are fascinated by the posttranslational modifier ubiquitin − a single, small protein that regulates myriad aspects of eukaryotic physiology with astounding precision. A major key to the specificity of ubiquitin modifications lies in the action of ubiquitin ligases (E3 enzymes). With about 1000 members in the human proteome, ubiquitin ligases are the most diverse class of ubiquitination enzymes and responsible for substrate selection and modification. The immense potential of ubiquitin ligases as therapeutic targets has been illustrated by the clinical efficacy of thalidomide and its derivatives in the treatment of hematological malignancies. However, progress towards rationally manipulating ubiquitin ligases for therapeutic benefit has been impeded largely by our insufficient understanding of their macromolecular complexes, conformational dynamics, and functional integration into cellular pathways.
While principles of regulation have begun to emerge for multi-component ubiquitin ligases of the RING family, the class of HECT-type ligases has lagged behind, not least because these large, single-chain enzymes are part of highly dynamic macromolecular assemblies. Our studies thus aim to understand these assemblies as prototypical interaction hubs that encode context-dependent specificity in cellular signaling. An orthogonal line of our research is directed at the development of chemical probes for the conformational dynamics and activities of HECT-type ligases with the exciting potential to target this yet undrugged class of enzymes therapeutically. To this end our laboratory uses a multi-disciplinary approach, combining cryo-electron microscopy and X-ray crystallography with biochemistry, chemical biology, and cell biology.
Our lab has relocated from the University of Würzburg to the Max Planck Institute for Multidisciplinary Sciences in Göttingen in March 2021. We are always interested in recruiting motivated PhD students and postdocs who are scientists at heart. Please get in touch with Sonja Lorenz by email if you are interested in joining us.