Tau is an intrinsically disordered microtubule-associated protein whose misfolding into insoluble filamentous aggregates is one of the two hallmarks of Alzheimer?s disease. In AD brains the tau neurofibrillary tangles are hyperphosphorylated, but how phosphorylation converts tau?s functional structure to its dysfunctional fibril structure is not well understood at the molecular level. We propose to extend the parent grant by investigating the structural dynamics of a proline-rich region of tau. This region has been implicated to play a significant role in microtubule binding and is known to contain many hyperphosphorylation sites of tau. We will study how this proline-rich domain changes its conformation and dynamics upon binding to microtubules, and how phosphorylation regulates the binding equilibrium and the conformational equilibrium. We will obtain this information by measuring solid-state NMR spectra of the proline-rich peptide in the free and bound states without and with phosphorylation. Molecular insights gained from this study will be integrated into our investigation of the full-length tau in the parent grant. 1
Misfolding of the protein tau in neuronal cells is associated with Alzheimer?s disease, which inflicts more than 5 million Americans. How tau converts from its functional state of an intrinsically disordered protein that interacts with neuronal microtubules to an aggregated ?- sheet rich protein remains poorly understood. We propose to investigate the conformation and dynamics of a proline-rich region of tau as bound to microtubules, to gain molecular insights into the initial events of tau aggregation. 1
