Folding of the Repeat Domain of Tau Upon Binding to Lipid Surfaces
Abstract
The microtubule-associated protein tau is impacted in neurodegeneration and dementia through its deposition in the form of paired helical filaments in Alzheimer's disease neurofibrillary tangles and through mutations linking it to the autosomal dominant disorder frontotemporal dementia with Parkinsonism. When isolated in solution tau is intrinsically unstructured and does not fold, while the conformation of the protein in the microtubule-bound state remains uncharacterized. Here we show that the repeat region of tau, which has been reported both to mediate tau microtubule interactions and to constitute the proteolysis-resistant core of disease-associated tau aggregates, associates with lipid micelles and vesicles and folds into an ordered structure upon doing so. In addition to providing the first structural insights into a folded state of tau, our results support a role for lipid membranes in mediating tau function and tau pathology.
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Tau residues 253-260, 315-322, and 345-354 populate helical structure in the presence of detergent and upon binding to membranes.
“Consistent with the compatibility of these regions for helical conformation, Tau residues 253–260, 315–322, and 345–354 populate helical structure in the presence of detergent and upon binding to membranes65.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [65]
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Role of the Lipid Membrane and Membrane Proteins in Tau Pathology
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- Authors
- Barré, P., & Eliezer, D.
- Affiliations
- Cornell University (US)
- Corresponding author
- Eliezer, David
- ORCID
- Eliezer, David
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 362
- Issue
- 2
- Pages
- 312-326
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2074952395
- Cited by
- 69
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 5 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 6
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG025440, R37AG019391, AG025440, R01AG019391)
- National Institute of General Medical Sciences (P41GM066354, GM 66354)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- tau protein, repeat domain, protein folding, lipid membranes, lipid micelles, lipid vesicles, microtubule binding, Alzheimer's disease, frontotemporal dementia, neurofibrillary tangles, paired helical filaments, intrinsically disordered proteins, protein-membrane interactions
- MeSH terms
- Amino Acid Sequence, Animals, Circular Dichroism, Humans, Lipids, Molecular Sequence Data, Peptide Fragments, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Surface Properties, tau Proteins, Protein Folding, Nuclear Magnetic Resonance, Biomolecular, Protein Isoforms
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