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Research Area A

Structures, Mechanisms and Dynamics of Membrane Complexes and Membranes

Membranes define the cell and its compartments. Proteins and protein complexes in these lipid bilayers carry out fundamental cellular functions, from basic energy conversion, active and passive uptake of metabolites, signal recognition and transduction, to cell-cell interaction and tissue formation. Frankfurt is one of the world´s leading centers in the study of membrane proteins, membrane complexes, and their molecular mechanisms. In CEF-I major breakthroughs were achieved in this demanding area, including a 6 Å map of mitochondrial complex I, high-resolution structures of cytochrome cbb3 oxidase, and of two new secondary transporters. In CEF-II, we will take advantage of the outstanding research environment, which enables us to study membrane protein complexes by x-ray crystallography, electronmicroscopy, and a wide range of biophysical and spectroscopic techniques, including EPR, liquid- and solid-state NMR spectroscopy. We will obtain structural and mechanistic information on different classes of membrane transport proteins and complexes, and intensify the detailed investigation of function and cooperativity in secondary transporters, as well as the structure and dynamics of the MHC-I antigen-loading complex. We will apply state-of-the-art light, correlative fluorescence and electron microscopy as well as electron cryo-tomography of whole organelles and membranes to image large complexes in situ. With these techniques we will describe the dynamic association of membrane proteins into large assemblies, and how the formation and disintegration of such assemblies governs membrane plasticity and cellular function. For this aim, we will focus on mitochondria and in particular address the dynamic changes and proteomic re-arrangements occurring in this organelle during the transition that precedes programmed cell death. The downstream events of apoptosis will be investigated in Research Area B.

Strategic Goals:

• New and improved membrane protein structures
• Structure-based functional analysis incorporating theoretical modeling approaches
• Emphasis on lipid-protein interactions and membrane dynamics
• Structural and proteomic investigation of large and dynamic macromolecular complexes
• Integration into organellar/cellular context and translation to disease and aging models