Characterization of Alzheimer’s-like Paired Helical Filaments from the Core Domain of Tau Protein Using Solid-State NMR Spectroscopy
Abstract
The polymerization of the microtubule-associated protein tau into paired helical filaments (PHFs) represents one of the hallmarks of Alzheimer's disease. We employed solid-state nuclear magnetic resonance (NMR) to investigate the structure and dynamics of PHFs formed in vitro by the three-repeat-domain (K19) of protein tau, representing the core of Alzheimer PHFs. While N and C termini of tau monomers in PHFs are highly dynamic and solvent-exposed, the rigid segment consists of three major beta-strands. Combination of through-bond and through-space ssNMR transfer methods with water-edited ((15)N, (13)C) and ((13)C, (13)C) correlation experiments suggests the existence of a fibril core that is largely built by repeat unit R3, flanked by surface-exposed units R1 and R4. Solid-state NMR, circular dichroism, and the fibrillization behavior of a K19 mutant furthermore indicate that electrostatic interactions play a central role in stabilizing the K19 PHFs.
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The hexapeptide 275VQIINK280 populates extended structure in solution, is found in cross-β structure in amyloid fibrils, but folds into helical structure in complex with F-actin.
“The hexapeptide populates extended structure in solution27, is found in cross-β structure in amyloid fibrils63, but folds into helical structure in complex with F-actin (Fig. 3d).”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [63]
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Sites of Tau Important for Aggregation Populate β-Structure and Bind to Microtubules and Polyanions
Mukrasch, M. D., Biernat, J., von Bergen, M., Griesinger, C., Mandelkow, E., & Zweckstetter, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501565200 · Cited by 324 · see citing works
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Structural Polymorphism of 441-Residue Tau at Single Residue Resolution
Mukrasch, M. D., Bibow, S., Korukottu, J., Jeganathan, S., Biernat, J., Griesinger, C., Mandelkow, E., & Zweckstetter, M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000034 · Cited by 652 · see citing works
Self-citationCabrales Fontela, Y., Kadavath, H., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-02230-8 · Cited by 148 · see citing works
Self-citationVariations in filament conformation dictate seeding barrier between three- and four-repeat Tau
Dinkel, P. D., Siddiqua, A., Huynh, H., Shah, M., & Margittai, M. (2011) · Biochemistry · doi:10.1021/bi2004685 · Cited by 104 · see citing works
- Authors
- Andronesi, O. C., Bergen, M. V., Biernat, J., Seidel, K., Griesinger, C., Mandelkow, E., & Baldus, M.
- Affiliations
- Deutsches Elektronen-Synchrotron DESY (DE)
- Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany, and Max Planck Unit for Structural Molecular Biology at DESY, 22607 Hamburg, Germany
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-04-03
- Volume
- 130
- Issue
- 18
- Pages
- 5922-5928
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2015795135
- Cited by
- 167
- References
- 2
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 10 · 2019: 13 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 6 · 2014: 7 · 2013: 10 · 2012: 9
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- paired helical filaments, tau protein, Alzheimer's disease, beta-strand, electrostatic interactions, fibril stability, protein dynamics, microtubule-associated proteins
- MeSH terms
- Alzheimer Disease, Circular Dichroism, tau Proteins, Protein Structure, Secondary, Protein Structure, Tertiary, Nuclear Magnetic Resonance, Biomolecular
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