Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure

• Published in: JACS Au Vol. 2; no. 3; pp. 673 - 686
• Main Authors: Stelzl, Lukas S, Pietrek, Lisa M, Holla, Andrea, Oroz, Javier, Sikora, Mateusz, Köfinger, Jürgen, Schuler, Benjamin, Zweckstetter, Markus, Hummer, Gerhard
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28-03-2022
• Subjects: molecular dynamics simulations; tauopathy; NMR; intrinsically disordered protein; Alzheimer’s disease; tau; FRET; SAXS
• ISSN: 2691-3704; 2691-3704
• DOI: 10.1021/jacsau.1c00536

The paradigmatic disordered protein tau plays an important role in neuronal function and neurodegenerative diseases. To disentangle the factors controlling the balance between functional and disease-associated conformational states, we build a structural ensemble of the tau K18 fragment containing the four pseudorepeat domains involved in both microtubule binding and amyloid fibril formation. We assemble 129-residue-long tau K18 chains with atomic detail from an extensive fragment library constructed with molecular dynamics simulations. We introduce a reweighted hierarchical chain growth (RHCG) algorithm that integrates experimental data reporting on the local structure into the assembly process in a systematic manner. By combining Bayesian ensemble refinement with importance sampling, we obtain well-defined ensembles and overcome the problem of exponentially varying weights in the integrative modeling of long-chain polymeric molecules. The resulting tau K18 ensembles capture nuclear magnetic resonance (NMR) chemical shift and J-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.