Deciphering the regulatory code of transcription

• Antragsteller: Professor Dr. Tobias Madl
• Fachliche Zuordnung: Strukturbiologie
• Förderung: Förderung von 2012 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 217655988

My research project centers on the molecular mechanisms by which intrinsically disordered proteins, in particular transcription factors, are acting as key regulators of cell and organismal fate, and how they contribute to diseases and ageing. My focus is on the two transcription factors that link the regulatory Wnt pathway with insulin signaling and oxygen metabolism: i) Forkhead box O (FOXO) and ii) T Cell Factor/Lymphoid Enhancer-Binding Factor (TCF/LEF). Whereas FOXO can act as tumor suppressor and extend lifespan, TCF/LEF can stimulate cell proliferation and cancer. Control of the molecular mechanisms at the intersection of the insulin and Wnt signaling pathways holds a great potential for disease treatment. However, the underlying molecular mechanisms are still largely unknown. Here, I propose to study the molecular details of regulated binding of key FOXO and TCF/LEF co-factors to the unstructured regions of FOXO and TCF/LEF in vitro and the functional implications in vivo. I employ to this end my novel Nuclear Magnetic Resonance spectroscopy, Small-angle X-ray/neutron scattering and modeling strategies which are especially suited to study the structure of protein complexes involving intrinsically disordered regions (IDRs). The results will provide insight into the binding of an IDR of a transcription factor to co-factors and the role herein of post-translational modification. This will generate general knowledge on protein-protein interactions involving IDRs and provide insight how these interactions can be targeted by inhibitors.Finally, this will provide insight into regulation of FOXO and TCF/LEF function and thereby insight into the intricate link between lifespan and disease. Taken together, this will set a sound base for my new internationally-leading research group.

• DFG-Verfahren: Emmy Noether-Nachwuchsgruppen