NMR-basierte Charakterisierung phosphorylierungsinduzierter, konformationeller Übergänge in dem Alzheimer-assozierten Protein Tau

• Applicant: Professor Dr. Markus Zweckstetter
• Subject Area: Structural Biology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 185614764

The Tau protein, which is a microtubule-associated intrinsically disordered protein, plays a central role in the progression of Alzheimer disease. In Alzheimer disease, Tau becomes excessively phosphorylated, loses its ability to bind to microtubuli, and aggregates into intracellular abnormal protein deposits. Considerable effort has been made over the years to investigate the impact of phosphorylation on the structure of Tau as a means to understand its function and mechanisms of action, but these efforts have primarily used traditional biochemistry approaches and therefore have addressed structure and function at a relatively primitive level. Recently, we have shown that it is possible to study the structure and dynamics of 441-residue Tau at single residue resolution using NMR spectroscopy. Here we propose to develop a self-consistent molecular ensemble description of Tau that combines and reflects multiple complementary conformationally-dependent experimental parameters. We will then use this description as a basic building block to reveal the transition from apparent normality into the diseased state of Tau. The proposed project will provide unprecedented insight into the conformational changes that are associated with pathogenic misfolding of Tau.

• DFG Programme: Research Grants