Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites.
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 by Pin1, a peptidyl-prolyl isomerase that stimulates dephosphorylation 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.
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Taeko
T
Kimura
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Koji
K
Tsutsumi
Department of Chemistry, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Masato
M
Taoka
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Taro
T
Saito
Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
Masami
M
Masuda-Suzukake
Mitsubishi Kagaku Institute of Life Science, Machida, Tokyo 194-8511, Japan.
Koichi
K
Ishiguro
University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070.
Florian
F
Plattner
Department of Molecular Cell Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 981-8555, Japan.
Takafumi
T
Uchida
Department of Chemistry, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Toshiaki
T
Isobe
Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
Masato
M
Hasegawa
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan. Electronic address: hisanaga-shinichi@tmu.ac.jp.
Shin-Ichi
SI
Hisanaga
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
C054369:MAPT protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020033:Protein Isoforms; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse