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TRR 186:  Molecular Switches: Spatio-temporal Control of Cellular Signal Transmission

Subject Area Biology
Chemistry
Medicine
Term since 2016
Website Homepage
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 278001972
 
Biological information processing relies on the implementation of molecular switches along the cell’s signaling pathways. As a result of conformational changes, lipid or post-translational modifications, induced oligomerization, altered Ca2+ levels or changed redox conditions, the spatiotemporal patterning of molecules, macromolecular complexes or whole organelles within the living cell will be changed. Understanding this complex dynamic adaptation not only requires an intimate knowledge of a molecular switch and its mode of action, but also an understanding of the upstream and downstream biological processes that are linked to individual switching events. For example, post-translational modifications can be single- or multi-site, they can be specific or promiscuous and they can give rise to fast or slow responses. Conceptualizing the different cellular contexts that require the distinct types of molecular switches is a primary goal of our research consortium. Its realization depends on advanced technology that on the one hand allows for the acquisition of high-resolution images at the molecular and cellular level and on the other hand captures the dynamic changes in these structures. Cryo-electron microscopy and tomography will become important methodologies of TRR186 that allow for pinpointing molecular switching mechanisms in the context of large macromolecular assemblies at atomic resolution. Super-resolution light microscopy enables researchers to observe cellular architectures, for example in vesicular transport or at organellar contact sites. Correlative light and electron microscopy combines molecular and cellular imaging techniques and further pushes the limits of what can be observed in certain projects of TRR186. Dynamic aspects of cellular behavior are addressed by using stimulated emission depletion (STED), MinFlux or single molecule super-resolution microscopy, while molecular dynamics simulations and Markov State Modeling are suitable to describe the conformational landscape at the molecular level. Cellular switching behavior is conceptualized by mathematical modeling of signaling pathways, taking into account essential features, as for example the negative feed-back loops characteristic for oscillatory behavior. Ultimately, all projects will put their findings in the context of a biological process, ranging from neurotransmission, vesicle formation and secretion to receptor proximal signaling in immune cells, RNA surveillance and oscillations in virus-infected cells or in the circadian clock. Therefore, combining the knowledge about the principal building units of information processing in living systems with a cellular understanding of their prerequisites and consequences will allow us to carry the concept of molecular switches to a level from where we are better able to understand and manipulate complex cellular behavior in health and disease.
DFG Programme CRC/Transregios
International Connection Denmark

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Applicant Institution Freie Universität Berlin
Participating University Charité - Universitätsmedizin Berlin
Co-Applicant Institution Ruprecht-Karls-Universität Heidelberg
Spokespersons Professor Dr. Christian Freund, since 7/2022; Professor Dr. Walter Nickel, until 6/2022
 
 

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