SFB 1381: Dynamic organization of cellular protein machineries: From biogenesis and modular assembly to function

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Complex biological functions are performed by multiprotein assemblies that act as molecular machineries. Their functions encompass all aspects of cellular physiology from DNA replication, repair and transcription to protein translation, folding and degradation, the conversion of energy and the transport of molecules, to the communication via signal transduction between organelles and cells. While technological advancements resulted in the identification of a plethora of different subunits and protein-protein interactions, the challenge remains to identify the step-wise assembly of the individual subunits into macromolecular complexes and the functional gain that these assemblies provide that is far more than the sum of their individual proteins. In addition, protein machineries are not static entities, but can dynamically associate with other complexes to form a network of assemblies. They can also partially or fully disassemble in response to binding of ligands or second messengers or changes within the metabolic state of the cell. In the CRC1381 we aim to address the challenging open questions of the dynamic organization of protein machineries. Our interdisciplinary approach combines molecular and cell biology, biophysics, and structural biology and enables us to comprehensively analyze the biogenesis and assembly of complex protein machineries on the molecular level up to the investigation of the functional outputs and regulatory controls that cellular demands exert on them. With this unique expertise the CRC1381 investigates i) how multiprotein machineries are assembled into functional units during biogene-sis, ii) how modular assemblies impact on function and iii) how these assemblies are integrated into dynamic cellular networks and controlled by external stimuli to adapt the cell to cellular demands. In the first funding period we generated detailed molecular insights into the composition of the investigated machineries: We uncovered missing protein components and identified novel subassemblies that mediate different functional outputs. In the second funding period we want to expand our molecular and mechanistic analysis towards integration of cellular dynamics and cellular signaling to investigate the assembled protein machineries and their different modules in the spatial and temporal cellular context. For this we will combine our core expertise with advanced microscopy techniques to address the questions how submodules are formed dynamically and at different localizations in the cell, how assembly and disassembly is regulated by signaling pathways, and how cellular protein machineries adapt their function to changes in cellular states. Building on our multidisciplinary expertise, we propose a comprehensive, and highly integrative research approach to uncover the mechanisms in biogenesis and function of multiprotein assemblies that govern the cellular processes of life.