Isomerase Pin1 stimulates dephosphorylation of Tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites

Taeko Kimura, Koji Tsutsumi, Masato Taoka, Taro Saito, Masami Masuda-Suzukake, Koichi Ishiguro, Florian Plattner, Takafumi Uchida, Toshiaki Isobe, Masato Hasegawa, Shin Ichi Hisanaga

Research output: Contribution to journalArticle

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Abstract

Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. Alzheimer disease, the most common tauopathy, is characterized by neurofibrillary tangles that are mainly composed of abnormally phosphorylated Tau. Similar hyperphosphorylated Tau lesions are found in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) that is induced by mutations within the tau gene. To further understand the etiology of tauopathies, it will be important to elucidate the mechanism underlying Tau hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3β and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced byPin1,apeptidyl-prolylisomerasethat stimulatesdephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present, Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) despite the presence of many more hyperphosphorylated sites. Here, we analyzed the interaction of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202, Thr-205, Ser-235, and Ser-404). Furthermore, FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau, suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the interaction between Pin1 and Tau. Together, these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies.

Original languageEnglish (US)
Pages (from-to)7968-7977
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number11
DOIs
StatePublished - Mar 15 2013

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Tauopathies
tau Proteins
Frontotemporal Dementia
Isomerases
Phosphorylation
Cyclin-Dependent Kinases
Proline
Neurodegenerative diseases
Protein Phosphatase 2
Microtubule-Associated Proteins
Chromosomes
Protein Kinases
Assays
Alzheimer Disease
Agglomeration
Genes
Chromosomes, Human, Pair 17
Mutation
Neurofibrillary Tangles
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Isomerase Pin1 stimulates dephosphorylation of Tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites. / Kimura, Taeko; Tsutsumi, Koji; Taoka, Masato; Saito, Taro; Masuda-Suzukake, Masami; Ishiguro, Koichi; Plattner, Florian; Uchida, Takafumi; Isobe, Toshiaki; Hasegawa, Masato; Hisanaga, Shin Ichi.

In: Journal of Biological Chemistry, Vol. 288, No. 11, 15.03.2013, p. 7968-7977.

Research output: Contribution to journalArticle

Kimura, T, Tsutsumi, K, Taoka, M, Saito, T, Masuda-Suzukake, M, Ishiguro, K, Plattner, F, Uchida, T, Isobe, T, Hasegawa, M & Hisanaga, SI 2013, 'Isomerase Pin1 stimulates dephosphorylation of Tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites', Journal of Biological Chemistry, vol. 288, no. 11, pp. 7968-7977. https://doi.org/10.1074/jbc.M112.433326
Kimura, Taeko ; Tsutsumi, Koji ; Taoka, Masato ; Saito, Taro ; Masuda-Suzukake, Masami ; Ishiguro, Koichi ; Plattner, Florian ; Uchida, Takafumi ; Isobe, Toshiaki ; Hasegawa, Masato ; Hisanaga, Shin Ichi. / Isomerase Pin1 stimulates dephosphorylation of Tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 11. pp. 7968-7977.
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AU - Masuda-Suzukake, Masami

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