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Cited by 42Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingElectron Spin Resonance Studies

Single Mutations in Tau Modulate the Populations of Fibril Conformers through Seed Selection

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Meyer, Virginia, Dinkel, Paul D., Luo, Yin, Yu, Xiang, Wei, Guanghong, Zheng, Jie, Eaton, Gareth R., Ma, Buyong +3 more·2014·Angewandte Chemie International Edition
DOI 10.1002/anie.201308473PMC PMC4083751
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Abstract

Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer’s disease and other neurodegenerative disorders. Self‐assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron‐electron resonance spectroscopy was used to investigate the conformational ensemble of four‐repeat tau fibrils. Single point mutations at key positions in the protein (ΔK280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template‐assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation.

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Crossref · 10.1002/anie.201308473

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  • The specific folded tau could be energetically more favourable for accelerated transformation of ptau to NFT tau in the presence of additional proteinopathy such as Aβ.

    “This may be related to the fact that this specific type of folded tau could be energetically more favourable for accelerated transformation of ptau to NFT tau in the presence of additional proteinopathy such as Aβ (26, 27).”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [27]

    The Abstract reports that conformational compatibility influences seeded conversion of tau monomers into fibrils. It does not establish that a particular folded tau is energetically more favourable, or that Aβ accelerates conversion of phosphorylated tau into neurofibrillary tangles. (LLM, conf=0.84)

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Authors
Meyer, V., Dinkel, P. D., Luo, Y., 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)
  • National Cancer Institute (US)
  • Tel Aviv University (IL)
Corresponding author
Margittai, Martin
ORCID
Venue
Angewandte Chemie International Edition
Publisher
Wiley
Published
2014-01-22
Volume
53
Issue
6
Pages
1590-1593
ISSN
  • 1433-7851 (ISSN-L)
  • 1521-3773
DOI
10.1002/anie.201308473
PMC
PMC4083751
OpenAlex
W2126199560
Cited by
42
References
8
Citations by year
2024: 1 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 5
FWCI
4.65
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Angewandte Chemie International Edition (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (HHSN261200800001C)
  • National Cancer Institute (HHSN261200800001E))
  • National Institute of Neurological Disorders and Stroke (R01NS076619)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electron Spin Resonance Studies
Keywords
tau protein, tau fibrils, seeded aggregation, seed selection, point mutations, microtubule-binding repeats, template-assisted growth, Alzheimer's disease, tauopathy, double electron-electron resonance
MeSH terms
Electron Spin Resonance Spectroscopy, Humans, Mutation, Protein Binding, Spin Labels, tau Proteins, Protein Structure, Secondary, Amino Acid Substitution, Protein Isoforms

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