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Structural role of post-traductional modification on tau physio-pathological function

Our objective is to link Tau MAP function with structural and dynamics determinant: how is Tau structured on MTs and how its dynamics affects its MAP function in solution and in living cells. Regarding post-translational modifications, the classical approaches to the study of Tau phosphorylations are to evaluate the impact of a set of phosphorylation knowing that it is very difficult to phosphorylate only one specific site on the protein at the molecular level. The novelty of this project resides in our ability to analysis the impact of only one specific phosphorylation at a time at molecular level. We will then first focus on the specific Alzheimer AT8 epitope, of the Tau protein, largely involved in neurodegenerative diseases to understand the link between structural parameters and functional consequences. We will used Site-Directed Spin Labeling combined with Electron Paramagnetic Resonance (SDSL-EPR) spectroscopy (in collaboration with V. Belle, UMR7281) to monitor the structural dynamics of Tau and the effect of PTMs on its interaction with MTs, Nuclear Magnetic Resonance (NMR) spectroscopy to characterize Tau PTMs, their structural impact in solution and the region of Tau bound to MTs (In collaboration with I. Landrieu, UMR8576). We will used quantitative assays of tubulin polymerization to quantify the tau function, microcalorimetry and fluorescence spectroscopy to measure thermodynamic parameters of its interaction with MTS/tubulin.

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