Tau domains, phosphorylation, and interactions with microtubules
Abstract
We consider the interactions of tau protein with microtubules from two points of view, phosphorylation and domain structure. Tau can be phosphorylated at many sites and by several kinases, notably by proline-directed kinases (MAPK, GSK-3, cdk5) which generate Alzheimer-like antibody epitopes. Other kinases phosphorylate Ser 262, a site that has a particularly pronounced influence on the affinity of tau for microtubules. All of these sites can be cleared by phosphatases PP-2a and calcineurin. The site Ser262 lies within the repeat domain of tau. However, when probing the domains of tau for their effects on microtubule binding, nucleation, assembly, or bundling, the repeat domain has only a weak influence. Whereas the repeat domain of tau binds to microtubules with low affinity, repeat-less tau binds strongly yet unproductively in terms of microtubule assembly. Productive binding of tau to microtubules depends on the combination of (some) repeats with the flanking regions, as if the flanking regions acted as "jaws" for the proper positioning of tau on the microtubule surface.
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Tau is phosphorylated at numerous residues and at different developmental stages, and individual tau molecules often exhibit heterogeneous phosphorylation patterns.
“Tau is phosphorylated at numerous residues and at different developmental stages, and individual tau molecules often exhibit heterogeneous phosphorylation patterns”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Mandelkow et al., 1995
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Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Mandelkow, E.-M., Biernat, J., Drewes, G., Gustke, N., Trinczek, B., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 1995-05
- Volume
- 16
- Issue
- 3
- Pages
- 355-362
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2090879587
- Cited by
- 308
- References
- 3
- Citations by year
- 2026: 12 · 2025: 4 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 14 · 2019: 18 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 7
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau phosphorylation, microtubule binding, repeat domain, proline-directed kinases, mitogen-activated protein kinase, glycogen synthase kinase-3, cyclin-dependent kinase 5, phosphatase, protein phosphatase 2A, calcineurin, Alzheimer's disease, microtubule assembly, microtubule bundling
- MeSH terms
- Animals, Humans, Microtubules, Phosphorylation, Protein Binding, tau Proteins
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