Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif ( 306 VQIVYK 311 ) forming β structure
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We have searched for a minimal interaction motif in τ protein that supports the aggregation into Alzheimer-like paired helical filaments. Digestion of the repeat domain with different proteases yields a GluC-induced fragment comprising 43 residues (termed PHF43), which represents the third repeat of τ plus some flanking residues. This fragment self assembles readily into thin filaments without a paired helical appearance, but these filaments are highly competent to nucleate bona fide PHFs from full-length τ. Probing the interactions of PHF43 with overlapping peptides derived from the full τ sequence yields a minimal hexapeptide interaction motif of 306 VQIVYK 311 at the beginning of the third internal repeat. This motif coincides with the highest predicted β-structure potential in τ. CD and Fourier transform infrared spectroscopy shows that PHF43 acquires pronounced β structure in conditions of self assembly. Point mutations in the hexapeptide region by proline-scanning mutagenesis prevent the aggregation. The data indicate that PHF assembly is initiated by a short fragment containing the minimal interaction motif forming a local β structure embedded in a largely random-coil protein.
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Hexapeptide VQIINK motifs in the second repeat and VQIVYK in the third repeat within the tau microtubule-binding domain are crucial for the formation of β-sheet structures and consequent tau aggregation.
“Hexapeptide VQIINK motifs in the second repeat and VQIVYK in the third repeat within the tau microtubule-binding domain are crucial for the formation of β-sheet structures and consequent tau aggregation [221, 222].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [222]
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Alonso, A. D., Beharry, C., Corbo, C. P., & Cohen, L. S. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.12.014 · Cited by 53 · see citing works
Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer’s Disease
Huseby, C. J., Hoffman, C. N., Cooper, G. L., Cocuron, J.-C., Alonso, A. P., Thomas, S. N., Yang, A. J., & Kuret, J. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-190604 · Cited by 54 · see citing works
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Chen, H.-H., Liu, P., Auger, P., Lee, S.-H., Adolfsson, O., Rey-Bellet, L., Lafrance-Vanasse, J., Friedman, B. A., Pihlgren, M., Muhs, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-35130-y · Cited by 51 · see citing works
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Lin, E. I., & Shell, M. S. (2010) · The Journal of Physical Chemistry B · doi:10.1021/jp104114n · Cited by 12 · see citing works
- Authors
- von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E.-M., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany; Institut fur Biochemie, Justus-Liebig-Universität, 35392 Giessen, Germany; and Institut fur Biologische Informationsverarbeitung 2, Forschungszentrum, 52428 Julich, Germany
- Max Planck Society (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-05-09
- Volume
- 97
- Issue
- 10
- Pages
- 5129-5134
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC25793
- OpenAlex
- W2142366168
- Cited by
- 1,021
- References
- 39
- Citations by year
- 2026: 45 · 2025: 47 · 2024: 48 · 2023: 60 · 2022: 53 · 2021: 69 · 2020: 62 · 2019: 75 · 2018: 65 · 2017: 44 · 2016: 45 · 2015: 37 · 2014: 40 · 2013: 28 · 2012: 40
- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- tau protein, paired helical filaments, Alzheimer's disease, protein aggregation, beta-structure, nucleation, repeat domain, self-assembly
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Circular Dichroism, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Recombinant Proteins, Amyloid beta-Peptides, Mutagenesis, Site-Directed, tau Proteins, Point Mutation, Protein Structure, Secondary, Spectroscopy, Fourier Transform Infrared, Repetitive Sequences, Amino Acid
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