Project Details
TRR 186: Molecular Switches: Spatio-temporal Control of Cellular Signal Transmission
Subject Area
Biology
Chemistry
Medicine
Chemistry
Medicine
Term
since 2016
Website
Homepage
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 278001972
A hallmark of cellular physiology is the coordination of signal transmission in space and time. Biological signals are generated by molecular switches cells employ to exert spatio-temporal control over a wide range of cellular processes. Prominent examples are protein secretion, endocytosis, receptor downstream signaling and circadian gene expression, among others. Typical examples for molecular switches include post-translational modifications produced by protein and lipid kinases, GTPases as well as calcium and redox switches. In this way, cells turn on and off signals that are required to coordinate cellular processes and responses to extracellular signals in space and time. On the one hand, this enables cells to dynamically organize molecular components of signaling processes in nanodomains and to localize a given downstream process. On the other hand, molecular switches can be used by cells in a way that enables them to operate processes at proper time scales. Intriguingly, a relatively small set of distinct molecular switches is capable of controlling a large diversity of cellular processes with widely differing kinetics from milliseconds in neurotransmission to hours in circadian gene expression. While the molecular mechanisms by which molecular switches are turned on and off are known in great detail in many cases, the molecular mechanisms of how they coordinate the corresponding downstream processes in space and time are poorly understood. The overarching goal of our research consortium is to functionally analyze how a distinct set of molecular switches controls the spatio-temporal regulation of a diverse range of biological processes. Intriguingly, in many cases, the molecular events that are downstream of the activation of a molecular switch trigger a cellular switch such as cell fate decisions between survival and apoptosis. To investigate the molecular mechanisms that link molecular switches to cellular switches in living cells, we use advanced chemical biology tools such as photoactivatable membrane lipids. In addition, experimental setups are employed to synchronize protein transport through optogenetic control. Another example are approaches that allow for controlling protein activity by acute and reversible spatial sequestration of proteins of interest. These strategies are complemented by advanced biochemical reconstitution experiments, structural analyses as well as theoretical approaches such as kinetic modeling or molecular dynamics simulations. In this way, the dissection of the individual steps of a given process as determined by the assembly, activation and time-dependent localization of the key molecular components of a process in question will continue to be a major goal of the TRR186 consortium. With this advanced set of interdisciplinary methodologies, our long-term goal is to obtain a comprehensive understanding of how signals generated by activated molecular switches translate into the precise spatio-temporal coordination of cellular processes such as protein secretion, receptor signaling, endocytosis and gene expression as well as other central activities that characterize living cells.
DFG Programme
CRC/Transregios
Current projects
- A01 - Molecular switches in the spatio-temporal coordination of FGF2 recruitment and membrane translocation (Project Heads Ewers, Helge ; Nickel, Walter )
- A02 - Acute control of intracellular trafficking through Rab GTPases in living tissues in Drosophila (Project Heads Boutros, Michael ; Hiesinger, Peter Robin )
- A03 - Ca2+ and lipid control of synaptic vesicle fusion (Project Heads Schultz, Carsten ; Sigrist, Stephan J. ; Walter, Alexander )
- A04 - Neurotransmitter release: Spatio-temporal characterization of membrane fusion intermediates (Project Heads Rosenmund, Christian ; Söllner, Thomas )
- A05 - The palmitoylation switch in activated T cells (Project Heads Brügger, Britta ; Freund, Christian )
- A06 - Spatio-temporal control of CD95-activation mode (Project Heads Ewers, Helge ; Martin-Villalba, Ana )
- A08 - Phosphoinositide-based switches in endolysosomal membrane dynamics and signaling (Project Heads Haucke, Ph.D., Volker ; Schultz, Carsten )
- A12 - Machine-learned coarse-grained molecular dynamics of the exocytosis machinery (Project Heads Clementi, Ph.D., Cecilia ; Noé, Frank ; Plattner, Nuria )
- A14 - Molecular switches regulating stress granule oscillation (Project Heads Ruggieri, Ph.D., Alessia ; Stoecklin, Georg )
- A15 - Temporal control of spliceosome activity to modulate splicing switches (Project Heads Heyd, Florian ; Wahl, Markus C. )
- A16 - Functional characterization of the molecular timer of the circadian clock of Neurospora crassa (Project Heads Brunner, Michael ; Herzel, Hanspeter )
- A17 - Chemical control of PER2-CRY1 heterodimerization: impact on circadian oscillations (Project Heads Herzel, Hanspeter ; Kramer, Achim )
- A18 - Analysis of a SUMO switch in EGF receptor signaling (Project Heads Blüthgen, Nils ; Melchior, Frauke )
- A19 - STARD3 as a cellular switch determining organelle contact sites (Project Head Höglinger, Doris )
- A20 - Nanoscale regulation of small GTPase switches at the trans-Golgi network/recycling endosomal interface (Project Head Bottanelli, Ph.D., Francesca )
- A21 - Switching antigens by the exchange catalyst HLA-DM (Project Heads Freund, Christian ; Höfer, Thomas )
- A22 - Metabolic switches regulating NADPH availability and stress tolerance (Project Heads Dick, Tobias ; Ralser, Markus )
- A23 - Control of organelle biogenesis by the Lipin switch (Project Heads Daumke, Oliver ; Schuck, Sebastian )
- A24 - Molecular switches in the TGF-β signaling pathway – the role of inositol pyrophosphate messengers (Project Heads Fiedler, Dorothea ; Klingmüller, Ursula )
- Z02 - Quantitative image processing (Project Head Ewers, Helge )
- Z03 - Central Coordination (Project Heads Freund, Christian ; Nickel, Walter )
- Z04 - Tools to generate and study molecular switches in living cells (Project Heads Brügger, Britta ; Johnsson, Kai )
Completed projects
- A07 - Optical control of calcium switches that orchestrate fast signaling in the brain. (Project Heads Hegemann, Peter ; Plested, Andrew )
- A09 - Molecular switches in polarized sorting and signaling in intestinal epithelial cells (Project Heads Boulant, Steeve ; Haucke, Ph.D., Volker )
- A10 - Phosphoinositide switches in neurons: implications for membrane dynamics, axonal morphogenesis and the cortical actin cytoskeleton (Project Head Eickholt, Britta )
- A11 - Systematic characterization of phosphoinositide switches involved in T cell function (Project Heads Freund, Christian ; Gavin, Anne-Claude ; Russell, Robert B. )
- A13 - Elucidating the redox-proteolysis switch for transcriptional induction of the ubiquitin proteasome system (UPS) in space and time (Project Head Krüger, Elke Beate )
- Z01 - Molecular tools for fast switching of cellular events (Project Head Schultz, Carsten )
Applicant Institution
Ruprecht-Karls-Universität Heidelberg
Co-Applicant Institution
Freie Universität Berlin
Participating Institution
Charité - Universitätsmedizin Berlin; Deutsches Krebsforschungszentrum (DKFZ); Max-Delbrück-Centrum für Molekulare Medizin (MDC); Max-Planck-Institut für medizinische Forschung; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Sektion Strukturbiologie
Sektion Strukturbiologie
Spokespersons
Professor Dr. Christian Freund, since 7/2022; Professor Dr. Walter Nickel, until 6/2022