Phosphorylation of Tau at Both Thr 231 and Ser 262 Is Required for Maximal Inhibition of Its Binding to Microtubules
Abstract
The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tau hyperphosphorylation reduces Tau's ability to stabilize microtubules.
“Tau hyperphosphorylation reduces its ability to stabilize microtubules [3–5]”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [5]
Phosphorylation of Tau reduces its ability to bind and stabilize microtubules.
“In addition, phosphorylation of Tau reduces its ability to bind and stabilize microtubules [3–5].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [5]
Phosphorylation of tau at both Thr231 and Ser262 achieves maximal inhibition of microtubule binding in vitro.
“Phosphorylation of tau at both Thr231 and Ser262 achieves maximal inhibition of microtubule binding in vitro [95]”
Cites
Paudel, H. K., Lew, J., Ali, Z., & Wang, J. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49492-1 · Cited by 285 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Tau pathology in Alzheimer disease and other tauopathies
Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X., Khatoon, S., Li, B., Liu, F., Rahman, A., et al. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.09.008 · Cited by 1,037 · see citing works
Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806 · see citing works
Self-citationLiu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04391.x · Cited by 759 · see citing works
Self-citationA potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Yuzwa, S. A., Macauley, M. S., Heinonen, J. E., Shan, X., Dennis, R. J., He, Y., Whitworth, G. E., Stubbs, K. A., McEachern, E. J., Davies, G. J., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.96 · Cited by 717 · see citing works
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · 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
SARS‐CoV‐2 targets neurons of 3D human brain organoids
Ramani, A., Müller, L., Ostermann, P. N., Gabriel, E., Abida‐Islam, P., Müller‐Schiffmann, A., Mariappan, A., Goureau, O., Gruell, H., Walker, A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020106230 · Cited by 518 · see citing works
Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies
Brunden, K. R., Trojanowski, J. Q., & Lee, V. M.-Y. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2959 · Cited by 440 · see citing works
Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3203-08.2008 · Cited by 404 · see citing works
“Nicotinamide was shown to markedly reduce Thr231-phosphotau levels; this particular species of tau has been reported to interfere with microtubule polymerization (Sengupta et al., 1998; Cho and Johnson, 2004), and is a commonly used biomarker for AD found in CSF (Ewers et al.”
BackgroundInfluentialGong, C.-X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., & Iqbal, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5535 · Cited by 405 · see citing works
Self-citationThe Emerging Link between O-GlcNAc and Alzheimer Disease
Zhu, Y., Shan, X., Yuzwa, S. A., & Vocadlo, D. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.601351 · Cited by 267 · see citing works
Pei, J.-J., Braak, H., An, W.-L., Winblad, B., Cowburn, R. F., Iqbal, K., & Grundke-Iqbal, I. (2002) · Molecular Brain Research · doi:10.1016/s0169-328x(02)00488-6 · Cited by 247 · see citing works
Self-citationOchalek, A., Mihalik, B., Avci, H. X., Chandrasekaran, A., Téglási, A., Bock, I., Giudice, M. L., Táncos, Z., Molnár, K., László, L., et al. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0317-z · Cited by 225 · see citing works
Pei, J.-J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., & Cowburn, R. F. (2001) · Journal of Alzheimer's Disease · doi:10.3233/jad-2001-3107 · Cited by 165 · see citing works
Self-citationPuvenna, V., Engeler, M., Banjara, M., Brennan, C., Schreiber, P., Dadas, A., Bahrami, A., Solanki, J., Bandyopadhyay, A., Morris, J. K., et al. (2016) · Brain Research · doi:10.1016/j.brainres.2015.11.007 · Cited by 144 · see citing works
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex
Carlyle, B. C., Nairn, A. C., Wang, M., Yang, Y., Jin, L. E., Simen, A. A., Ramos, B. P., Bordner, K. A., Craft, G. E., Davies, P., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322360111 · Cited by 139 · see citing works
Pitt, J., Roth, W., Lacor, P., Smith, A. B., Blankenship, M., Velasco, P., De Felice, F., Breslin, P., & Klein, W. L. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.07.018 · Cited by 134 · see citing works
Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody
Yuzwa, S. A., Yadav, A. K., Skorobogatko, Y., Clark, T., Vosseller, K., & Vocadlo, D. J. (2011) · Amino Acids · doi:10.1007/s00726-010-0705-1 · Cited by 130 · see citing works
Rudrabhatla, P., Jaffe, H., & Pant, H. C. (2011) · The FASEB Journal · doi:10.1096/fj.11-181297 · Cited by 121 · see citing works
De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105 · see citing works
Ojala, J. O., Sutinen, E. M., Salminen, A., & Pirttilä, T. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.09.012 · Cited by 102 · see citing works
Azorsa, D. O., Robeson, R. H., Frost, D., hoovet, B. M., Brautigam, G. R., Dickey, C., Beaudry, C., Basu, G. D., Holz, D. R., Hernandez, J. A., et al. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-25 · Cited by 88 · see citing works
Tsujio, I., Zaidi, T., Xu, J., Kotula, L., Grundke-Iqbal, I., & Iqbal, K. (2005) · FEBS Letters · doi:10.1016/j.febslet.2004.11.097 · Cited by 80 · see citing works
Self-citationIijima-Ando, K., Zhao, L., Gatt, A., Shenton, C., & Iijima, K. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq068 · Cited by 72 · see citing works
The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration
Deger, J. M., Gerson, J. E., & Kayed, R. (2015) · Aging Cell · doi:10.1111/acel.12359 · Cited by 69 · see citing works
López‐González, I., Carmona, M., Blanco, R., Luna‐Muñoz, J., Martínez‐Mandonado, A., Mena, R., & Ferrer, I. (2013) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00627.x · Cited by 28 · see citing works
Retromer dysfunction at the nexus of tauopathies
Carosi, J. M., Denton, D., Kumar, S., & Sargeant, T. J. (2021) · Cell Death & Differentiation · doi:10.1038/s41418-020-00727-2 · Cited by 16 · see citing works
Killick, R., Hughes, T. R., Morgan, B. P., & Lovestone, S. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2012.11.008 · Cited by 17 · see citing works
Saleem, K., Xiao, Z., Zhu, B., Ren, Y., Yan, Z., & Feng, J. (2026) · Molecular Psychiatry · doi:10.1038/s41380-025-03225-4 · Cited by 10 · see citing works
“Tau hyperpho-sphorylation reduces its ability to stabilize microtubules [3 – 5] and increases its propensity to form aggregates [6].”
- Authors
- Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I., & Iqbal, K.
- Corresponding author
- Sengupta, Amitabha
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 1998-09
- Volume
- 357
- Issue
- 2
- Pages
- 299-309
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W1977879318
- Cited by
- 363
- References
- 1
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 17 · 2023: 18 · 2022: 15 · 2021: 20 · 2020: 29 · 2019: 15 · 2018: 11 · 2017: 12 · 2016: 11 · 2015: 16 · 2014: 14 · 2013: 11 · 2012: 20
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag008076-09, 5r01ag005892-16, 5r01ns018105-17)
- National Institute on Aging (AG-05892, AG 08076)
- National Institute of Neurological Disorders and Stroke (NS 18105)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- tau protein, phosphorylation, microtubule binding, glycogen synthase kinase-3, cyclin-dependent kinase 5, CaM kinase II, protein kinase A, protein kinase C, paired helical filaments, Alzheimer's disease, hyperphosphorylation, microtubule assembly
- MeSH terms
- Amino Acid Sequence, Animals, Binding, Competitive, Humans, Isomerism, Microtubule-Associated Proteins, Microtubules, Molecular Sequence Data, Phosphorylation, Protein Binding, Serine, Threonine, tau Proteins, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Cyclin-Dependent Kinases, Glycogen Synthase Kinase 3, Cyclin-Dependent Kinase 5, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
