Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure
Lukas S. Stelzl, Lisa M. Pietrek, Andrea Holla, Javier Oroz, Mateusz Sikora, Jürgen Köfinger, Benjamin Schuler, Markus Zweckstetter, Gerhard Hummer
Abstract
-coupling measurements. Without further fitting, we achieve very good agreement with measurements of NMR residual dipolar couplings. The good agreement with experimental measures of global structure such as single-molecule Förster resonance energy transfer (FRET) efficiencies is improved further by ensemble refinement. By comparing wild-type and mutant ensembles, we show that pathogenic single-point P301L, P301S, and P301T mutations shift the population from the turn-like conformations of the functional microtubule-bound state to the extended conformations of disease-associated tau fibrils. RHCG thus provides us with an atomically detailed view of the population equilibrium between functional and aggregation-prone states of tau K18, and demonstrates that global structural characteristics of this intrinsically disordered protein emerge from its local structure.