Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau.
Neurodegenerative tauopathies, including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein Tau. One group of tauopathies, known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), is directly associated with mutations of the gene tau. However, it is unknown why mutant Tau is highly phosphorylated in the patient brain. In contrast to in vivo high phosphorylation, FTDP-17 Tau is phosphorylated less than wild-type Tau in vitro. Because phosphorylation is a balance between kinase and phosphatase activities, we investigated dephosphorylation of mutant Tau proteins, P301L and R406W. Tau phosphorylated by Cdk5-p25 was dephosphorylated by protein phosphatases in rat brain extracts. Compared with wild-type Tau, R406W was dephosphorylated faster and P301L slower. The two-dimensional phosphopeptide map analysis suggested that faster dephosphorylation of R406W was due to a lack of phosphorylation at Ser-404, which is relatively resistant to dephosphorylation. We studied the effect of the peptidyl-prolyl isomerase Pin1 or microtubule binding on dephosphorylation of wild-type Tau, P301L, and R406W in vitro. Pin1 catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro sequences in a subset of proteins. Dephosphorylation of wild-type Tau was reduced in brain extracts of Pin1-knockout mice, and this reduction was not observed with P301L and R406W. On the other hand, binding to microtubules almost abolished dephosphorylation of wild-type and mutant Tau proteins. These results demonstrate that mutation of Tau and its association with microtubules may change the conformation of Tau, thereby suppressing dephosphorylation and potentially contributing to the etiology of tauopathies.
Yotsumoto
Kensuke
K
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397.
Saito
Taro
T
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397.
Asada
Akiko
A
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397.
Oikawa
Takayuki
T
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397; Laboratory of Molecular Neurobiology, Tokyo Metropolitan Institute of Psychiatry, Kamikitazawa, Setagaya, Tokyo 156-8585.
Kimura
Taeko
T
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397.
Uchida
Chiyoko
C
University Health Center, Ibaraki University, Mito, Ibaraki 310-8512.
Ishiguro
Koichi
K
Mitsubishi Kagaku Institute of Life Science, Machida, Tokyo 194-8511.
Uchida
Takafumi
T
Department of Molecular Cell Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi 981-8555, Japan.
Hasegawa
Masato
M
Laboratory of Molecular Neurobiology, Tokyo Metropolitan Institute of Psychiatry, Kamikitazawa, Setagaya, Tokyo 156-8585.
Hisanaga
Shin-Ichi
SI
From the Department of Biological Sciences, Faculty of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397. Electronic address: hisanaga-shinichi@tmu.ac.jp.
D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D008959:Models, Neurological; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010449:Peptide Mapping; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; C054369:MAPT protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011994:Recombinant Proteins; D016875:tau Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse