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

Stelzl, L. S., Pietrek, L. M., Holla, A., Oroz, J., Sikora, M., Köfinger, J., et al. (2022). Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure. JACS Au, 2(3), 673-686. doi:10.1021/jacsau.1c00536.

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Stelzl, Lukas S.1, 2, 3, 4, Author              
Pietrek, Lisa M.1, Author              
Holla, Andrea5, Author
Oroz, Javier6, 7, Author
Sikora, Mateusz1, 8, Author              
Köfinger, Jürgen1, Author              
Schuler, Benjamin9, Author
Zweckstetter, Markus6, 10, Author
Hummer, Gerhard1, 11, Author              
1Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
2Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany, ou_persistent22              
3KOMET 1, Institute of Physics, Johannes Gutenberg University Mainz, Mainz, Germany, ou_persistent22              
4Institute of Molecular Biology (IMB), Mainz, Germany, ou_persistent22              
5Department of Biochemistry, University of Zurich, Zurich, Switzerland, ou_persistent22              
6German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany, ou_persistent22              
7Rocasolano Institute for Physical Chemistry, CSIC, Madrid, Spain, ou_persistent22              
8Faculty of Physics, University of Vienna, Vienna, Austria, ou_persistent22              
9Department of Biochemistry and Department of Physics, University of Zurich, Zurich, Switzerland, ou_persistent22              
10Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany, ou_persistent22              
11Institute for Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany, ou_persistent22              


Free keywords: tau, intrinsically disordered protein, tauopathy, Alzheimer’s disease, molecular dynamics simulations, NMR, FRET, SAXS
 Abstract: 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.


Language(s): eng - English
 Dates: 2021-11-262022-03-01
 Publication Status: Published online
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/jacsau.1c00536
BibTex Citekey: stelzl_global_2022
 Degree: -



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Title: JACS Au
  Abbreviation : JACS Au
Source Genre: Journal
Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 2 (3) Sequence Number: - Start / End Page: 673 - 686 Identifier: ISSN: 2691-3704
CoNE: https://pure.mpg.de/cone/journals/resource/2691-3704