Phosphorylation of Human Tau Protein by Microtubule Affinity-Regulating Kinase 2
Abstract
Tau protein plays an important role in neuronal physiology and Alzheimer's neurodegeneration. Its abilities to aggregate abnormally, to bind to microtubules (MTs), and to promote MT assembly are all influenced by phosphorylation. Phosphorylation of serine residues in the KXGS motifs of Tau's repeat domain, crucial for MT interactions and aggregation, is facilitated most efficiently by microtubule-associated protein/microtubule affinity-regulating kinases (MARKs). Here we applied high-resolution nuclear magnetic resonance analysis to study the kinetics of phosphorylation of Tau by MARK2 and its impact on the structure and microtubule binding of Tau. We demonstrate that MARK2 binds to the N-terminal tail of Tau and selectively phosphorylates three major and five minor serine residues in the repeat domain and C-terminal tail. Structural changes induced by phosphorylation of Tau by MARK2 are highly localized in the proximity of the phosphorylation site and do not affect the global conformation, in contrast to phosphorylation in the proline-rich region. Furthermore, single-residue analysis of binding of Tau to MTs provides support for a model in which Tau's hot spots of MT interaction bind independently of each other and are differentially affected by phosphorylation.
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MARK2 phosphorylates full-length Tau at S262, S293, S305, S324, S356, and S416.
“The downfield chemical shift of phosphorylated residues (Fig. 4a) is in agreement with previous reports and confirms phosphorylation at S262, S293, S305, S324, S356, and S41654.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [54]
Cites
The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein
Lu, P.-J., Wulf, G., Zhou, X. Z., Davies, P., & Lu, K. P. (1999) · Nature · doi:10.1038/21650 · Cited by 721 · see citing works
Tau protein kinases: Involvement in Alzheimer's disease
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M.-L., Yardin, C., & Terro, F. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.003 · Cited by 631 · see citing works
Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
Rissman, R. A., Poon, W. W., Blurton-Jones, M., Oddo, S., Torp, R., Vitek, M. P., LaFerla, F. M., Rohn, T. T., & Cotman, C. W. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420640 · Cited by 543 · see citing works
Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies
Irwin, D. J., Cohen, T. J., Grossman, M., Arnold, S. E., Xie, S. X., Lee, V. M.-Y., & Trojanowski, J. Q. (2012) · Brain · doi:10.1093/brain/aws013 · Cited by 281 · see citing works
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Wegmann, S., Eftekharzadeh, B., Tepper, K., Zoltowska, K. M., Bennett, R. E., Dujardin, S., Laskowski, P. R., MacKenzie, D., Kamath, T., Commins, C., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201798049 · Cited by 1,102 · see citing works
Self-citationAmbadipudi, S., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-00480-0 · Cited by 782 · see citing works
Self-citationDendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · see citing works
Cabrales Fontela, Y., Kadavath, H., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-02230-8 · Cited by 148 · see citing works
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Oroz, J., Chang, B. J., Wysoczanski, P., Lee, C.-T., Pérez-Lara, Á., Chakraborty, P., Hofele, R. V., Baker, J. D., Blair, L. J., Biernat, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06880-0 · Cited by 100 · see citing works
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Tseng, J.-H., Xie, L., Song, S., Xie, Y., Allen, L., Ajit, D., Hong, J.-S., Chen, X., Meeker, R. B., & Cohen, T. J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.082 · Cited by 93 · see citing works
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Zhao, J., Huvent, I., Lippens, G., Eliezer, D., Zhang, A., Li, Q., Tessier, P., Linhardt, R. J., Zhang, F., & Wang, C. (2017) · Biophysical Journal · doi:10.1016/j.bpj.2017.01.024 · Cited by 87 · see citing works
- Authors
- Schwalbe, M., Biernat, J., Bibow, S., Ozenne, V., Jensen, M. R., Kadavath, H., Blackledge, M., Mandelkow, E., & Zweckstetter, M.
- Affiliations
- Max Planck Society (DE)
- German Center for Neurodegenerative Diseases (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- Centre National de la Recherche Scientifique (FR)
- German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany
- Corresponding author
- Zweckstetter, Markus
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-11-22
- Volume
- 52
- Issue
- 50
- Pages
- 9068-9079
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2046608553
- Cited by
- 78
- References
- 4
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 8 · 2023: 1 · 2022: 9 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 4 · 2014: 2
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- DZNE Pub (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (089703)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- tau protein, MARK2, protein phosphorylation, serine phosphorylation, microtubule binding, Alzheimer's disease, tau aggregation, repeat domain, N-terminal tail, C-terminal tail, proline-rich region, phosphorylation kinetics, protein conformational change
- MeSH terms
- Humans, Microtubules, Phosphorylation, tau Proteins, Protein Serine-Threonine Kinases, Nuclear Magnetic Resonance, Biomolecular
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