Hydrodynamic Radius Determination of Tau and AT8 Phosphorylated Tau Mutants: A Combined Simulation and Experimental Study

Lohberger, C.; Marien, J.; Bridot, C.; Prevost, C.; Allegro, D.; Tatoni, M.; Landrieu, I.; Smett-nocca, C.; Sacquin-Mora, S.; Barbier, P.

doi:10.1101/2025.02.22.639620

bioRxiv · 10.1101/2025.02.22.639620

Hydrodynamic Radius Determination of Tau and AT8 Phosphorylated Tau Mutants: A Combined Simulation and Experimental Study

Lohberger, C.·Marien, J.·Bridot, C.·Prevost, C.·Allegro, D.·Tatoni, M.·Landrieu, I.·Smett-nocca, C.·Sacquin-Mora, S.·Barbier, P.

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Abstract

Hyperphosphorylated Tau is a hallmark of Alzheimers disease leading to functional loss and fibrillar inclusions. We aim to understand how AT8 phosphorylation affects the Taus conformation and dynamics during early pathological transformation. We engineered an alanine Tau mutant to target specific phosphorylation sites restricted to the AT8 epitope, generating two distinct phosphorylation states. Using a combination of biophysical methods, and pCALVADOS forcefield, we found that AT8 phosphorylation do not alter the hydrodynamic radius or overall dynamics of Tau. Simulations revealed that local stiffening and extension at the AT8 epitope scale with phosphorylation extent. Interestingly, phosphorylation induces distant contact losses toward the N-terminus. This study advances our understanding of the structure-function-dynamics relationship of Tau in neurodegeneration.

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Lohberger, C., Marien, J., Bridot, C., Prevost, C., Allegro, D., Tatoni, M., Landrieu, I., Smett-nocca, C., Sacquin-Mora, S., Barbier, P.. 2025-02-27. Hydrodynamic Radius Determination of Tau and AT8 Phosphorylated Tau Mutants: A Combined Simulation and Experimental Study. https://doi.org/10.1101/2025.02.22.639620

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