Global Hairpin Folding of Tau in Solution
Abstract
The microtubule-associated protein tau stabilizes microtubules in its physiological role, whereas it forms insoluble aggregates (paired helical filaments) in Alzheimer's disease. Soluble tau is considered a natively unfolded protein whose residual folding and intramolecular interactions are largely undetermined. In this study, we have applied fluorescence resonance energy transfer (FRET) and electron paramagnetic resonance (EPR) to examine the proximity and flexibility of tau domains and the global folding. FRET pairs spanning the tau molecule were created by inserting tryptophans (donor) and cysteines (labeled with IAEDANS as an acceptor) by site-directed mutagenesis. The observed FRET distances were significantly different from those expected for a random coil. Notably, the C-terminal end of tau folds over into the vicinity of the microtubule-binding repeat domain, the N-terminus remains outside the FRET distance of the repeat domain, yet both ends of the molecule approach one another. The interactions between the domains were obliterated by denaturation in GdnHCl. Paramagnetic spin-labels attached in various domains of tau were analyzed by EPR and exhibited a high mobility throughout. The data indicate that tau retains some global folding even in its "natively unfolded" state, combined with the high flexibility of the chain.
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According to the paperclip structural model, the site near Ser199/Ser202/Thr205 folds and the N-terminal region is situated close to the MT-binding repeats.
“According to the paperclip structural model of Tau (Jeganathan et al., 2006), the site near Ser199/Ser202/Thr205 folds and the N-terminal region is situated close to the MT-binding repeats.”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Jeganathan et al., 2006
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- Authors
- Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H.-J., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, D-22607 Hamburg, Germany, and Department of Physics, University of Osnabruck, D-49069 Osnabruck, Germany
- Osnabrück University (DE)
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-01-28
- Volume
- 45
- Issue
- 7
- Pages
- 2283-2293
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2104034347
- Cited by
- 432
- References
- 6
- Citations by year
- 2026: 25 · 2025: 19 · 2024: 19 · 2023: 30 · 2022: 32 · 2021: 29 · 2020: 37 · 2019: 36 · 2018: 32 · 2017: 19 · 2016: 17 · 2015: 22 · 2014: 14 · 2013: 15 · 2012: 26
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- 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 › Biophysics › Electron Spin Resonance Studies
- Keywords
- tau protein, intrinsically disordered proteins, protein flexibility, domain interactions, Alzheimer's disease, paired helical filaments
- MeSH terms
- Circular Dichroism, Electron Spin Resonance Spectroscopy, Naphthalenesulfonates, Solutions, Mutagenesis, Site-Directed, tau Proteins, Protein Folding, Fluorescence Resonance Energy Transfer
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