Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites
Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites
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DOI：
10.1074/jbc.m112.433326
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发表时间：
2013-03-15
影响因子：
4.8
通讯作者：
Hisanaga, Shin-Ichi
中科院分区：
文献类型：
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作者：
Kimura, Taeko;Tsutsumi, Koji;Hisanaga, Shin-Ichi
与微管相关蛋白Tau的病理性聚集相关的神经退行性疾病被归类为tau病。阿尔茨海默病是最常见的肌萎缩侧索硬化症，其特征是神经原纤维缠结，主要由异常磷酸化的Tau组成。类似的过度磷酸化的Tau病变也发现在额颞叶痴呆患者中，与17号染色体相关的帕金森病(FTDP-17)是由tau基因突变引起的。为了进一步了解tauopathy的病因，阐明tau过度磷酸化的机制将是很重要的。Tau的磷酸化主要发生在脯氨酸导向的Ser/Thr位点，这些位点是GSK3β和CDK5等蛋白激酶的靶标。我们以前报道过，在CDK5介导的位点上，Tau的去磷酸化被PIN1所促进，PIN1是一种多肽-脯氨酸异构酶，它能刺激蛋白质磷酸酶2A在脯氨酸导向的位点上去磷酸化。Pin1缺乏被认为是导致阿尔茨海默病患者Tau过度磷酸化的原因。到目前为止，尽管存在更多的过度磷酸化位点，但只有两个Tau磷酸化位点(Thr-212和Thr-231)与Pin1结合。在这里，我们使用GST下拉实验和Biacore方法分析了Pin1与被CDK5-p25磷酸化的Tau的相互作用。我们发现Pin1在CDK5介导的所有位点(Ser-202、Thr-205、Ser-235和Ser-404)上都能结合并刺激Tau的去磷酸化。此外，FTDP-17突变体Tau(P301L或R406W)与Pin1的结合略弱于未突变的Tau，提示FTDP-17突变通过减少Pin1与Tau之间的相互作用而诱导过度磷酸化。综上所述，这些结果表明Pin1普遍参与了Tau过度磷酸化的调节，从而导致了tauopathy的病因学。
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 hyper-phosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3 beta and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced byPin1, a peptidyl-prolylisomerase 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.