Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to microtubules
Abstract
Aggregation of the microtubule-associated protein tau into neurofibrillary tangles is the pathological hallmark of a variety of dementias. For reasons not yet known, tau becomes excessively phosphorylated in Alzheimer's brains and as a result no longer binds properly to microtubules. Here we studied the impact of phosphorylation on the conformational and binding properties of the repeat region of tau (K18) that is necessary for microtubule assembly and forms the core of paired helical filaments. To mimic phosphorylation, we introduced four mutations of serine to glutamate residues at positions 262, 293, 324, and 356. NMR spectroscopy demonstrates that pseudophosphorylation at these sites modifies the structural properties in repeats 1 and 2, in particular for Gln265-Lys267. Gln265-Lys267 are in close proximity to Ser262, the phosphorylation site that most strongly attenuates binding to microtubules. In contrast, the pseudophosphorylation mimic of tau efficiently interacts with the polyanion heparin. Thus, phosphorylation of the repeat region of natively unfolded tau induces specific conformational changes that have a strong impact on its biological function and involvement in disease.
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Tau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.
“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”
Phosphorylation at Ser262 and Ser356 decreases tau binding to microtubules.
“Ser262 and Ser356 are located in the microtubule-binding domain, and phosphorylation at these sites decreases tau binding to microtubules [18, 19, 25, 26, 50, 51].”
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“In contrast, MARK-dependent phosphorylation of tau at S262 induces conformational changes around this phosphorylation site, altering tau structure and attenuating Frontiers in Neuroscience | www.frontiersin.org 2 January 2016 | Volume 10 | Article 3 microtubule binding (Fischer et al., 2009).”
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- Authors
- Fischer, D., Mukrasch, M. D., Biernat, J., Bibow, S., Blackledge, M., Griesinger, C., Mandelkow, E., & Zweckstetter, M.
- Affiliations
- Max Planck Institute for Biophysical Chemistry (DE)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Centre National de la Recherche Scientifique (FR)
- Max Planck Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85, 22607 Hamburg, Germany
- Corresponding author
- Zweckstetter, Markus
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-10-01
- Volume
- 48
- Issue
- 42
- Pages
- 10047-10055
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2082617925
- Cited by
- 149
- References
- 5
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 5 · 2019: 20 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 10
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- GRO (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
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, microtubule binding, neurofibrillary tangles, Alzheimer's disease, paired helical filaments, intrinsically disordered proteins, heparin binding, protein conformational change
- MeSH terms
- Alzheimer Disease, Binding Sites, Circular Dichroism, Humans, Microtubules, Models, Molecular, Mutation, Magnetic Resonance Spectroscopy, Phosphorylation, Protein Conformation, Serine, tau Proteins, Glutamic Acid
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