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Cited by 75Alzheimer's disease research and treatmentsElectron Spin Resonance StudiesProtein Structure and Dynamics

Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau

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Siddiqua, Ayisha, Luo, Yin, Meyer, Virginia, Swanson, Michael A., Yu, Xiang, Wei, Guanghong, Zheng, Jie, Eaton, Gareth R. +4 more·2012·Journal of the American Chemical Society
DOI 10.1021/ja303498qPMC PMC3381011
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Abstract

Tau pathology in Alzheimer's disease is intimately linked to the deposition of proteinacious filaments, which akin to infectious prions, have been proposed to spread via seeded conversion. Here we use double electron-electron resonance (DEER) spectroscopy in combination with extensive computational analysis to show that filaments of three- (3R) and four-repeat (4R) tau are conformationally distinct. Distance measurements between spin labels in the third repeat, reveal tau amyloid filaments as ensembles of known β-strand-turn-β-strand U-turn motifs. Whereas filaments seeded with 3R tau are structurally homogeneous, filaments seeded with 4R tau are heterogeneous, composed of at least three distinct conformers. These findings establish a molecular basis for the seeding barrier between different tau isoforms and offer a new powerful approach for investigating the composition and dynamics of amyloid fibril ensembles.

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  • Fibrils formed in the presence of heparin are heterogeneous ensembles.

    “fibrils formed in the presence of heparin are heterogeneous ensembles (51, 52)”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [52]

    The Experimental Procedures (Sample Preparation for DEER Experiments; page unavailable) state that the studied filaments were prepared with heparin. The Results (Tau Filaments Are Heterogeneous; page unavailable) identify multiple conformers in K18 filaments, but also report that filaments seeded with K19 were structurally homogeneous. The claim therefore overgeneralizes the finding to heparin-formed fibrils as a whole. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The fibrils employed in the current study are known to have different folds.

    “The fibrils that were employed in the current study are known to have different folds.”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [52]

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Authors
Siddiqua, A., Luo, Y., Meyer, V., Swanson, M. A., Yu, X., Wei, G., Zheng, J., Eaton, G. R., Ma, B., Nussinov, R., Eaton, S. S., & Margittai, M.
Affiliations
  • University of Denver (US)
  • Fudan University (CN)
  • University of Akron (US)
  • Frederick National Laboratory for Cancer Research (US)
  • Tel Aviv University (IL)
Corresponding author
Margittai, Martin
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2012-06-12
Volume
134
Issue
24
Pages
10271-10278
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja303498q
PMC
PMC3381011
OpenAlex
W2014858798
Cited by
75
References
9
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 1 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 8 · 2018: 6 · 2017: 3 · 2016: 10 · 2015: 7 · 2014: 11 · 2013: 9
FWCI
5.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Chemical Society (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute
  • National Science Foundation
  • National Institute of Neurological Disorders and Stroke
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electron Spin Resonance Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
tau protein, tau isoforms, four-repeat tau, amyloid fibrils, conformational heterogeneity, Alzheimer's disease
MeSH terms
Alzheimer Disease, Amyloid, Humans, Models, Molecular, Spectrum Analysis, tau Proteins, Protein Structure, Secondary, Protein Isoforms, Repetitive Sequences, Amino Acid

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