Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation
Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation
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DOI：
10.1111/j.1471-4159.2008.05716.x
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发表时间：
2009-01-01
影响因子：
4.7
通讯作者：
Takeda, Masatoshi
中科院分区：
文献类型：
--
作者：
Sadik, Golam;Tanaka, Toshihisa;Takeda, Masatoshi
微管相关蛋白tau是阿尔茨海默病脑神经元缠结的主要成分，但其形成的神经病理过程尚不清楚。以前，14-3-3蛋白被报道与tau结合。14-3-3蛋白质通常通过特定的丝氨酸/苏氨酸磷酸化基序结合其靶点。因此，研究了tau与14-3-3通过磷酸化介导的相互作用。在这项研究中，我们表明，蛋白激酶A（PKA）或蛋白激酶B（PKB）的tau的磷酸化增强tau与14-3-3在体外的结合。如通过真实的时间表面等离子体共振研究确定的，tau和14-3-3之间的亲和力通过磷酸化增加12至14倍。突变分析显示，Ser 214对于tau与14-3-3的磷酸化介导的相互作用至关重要。最后，体外聚集测定表明，PKA/PKB磷酸化抑制14-3-3诱导的tau聚集体/细丝的形成。由于Ser 214的磷酸化在胎脑中上调，tau与14-3-3的相互作用可能在发育中微管细胞骨架的组织中起重要作用。此外，由于Ser 214处的磷酸化在阿尔茨海默病脑中上调，tau与14-3-3的相互作用可能参与这种疾病的病理学。
The microtubule associated protein tau is a major component of neurofibrillary tangles in Alzheimer disease brain, however the neuropathological processes behind the formation of neurofibrillary tangles are still unclear. Previously, 14-3-3 proteins were reported to bind with tau. 14-3-3 Proteins usually bind their targets through specific serine/threonine -phosphorylated motifs. Therefore, the interaction of tau with 14-3-3 mediated by phosphorylation was investigated. In this study, we show that the phosphorylation of tau by either protein kinase A (PKA) or protein kinase B (PKB) enhances the binding of tau with 14-3-3 in vitro. The affinity between tau and 14-3-3 is increased 12- to 14-fold by phosphorylation as determined by real time surface plasmon resonance studies. Mutational analyses revealed that Ser214 is critical for the phosphorylation-mediated interaction of tau with 14-3-3. Finally, in vitro aggregation assays demonstrated that phosphorylation by PKA/PKB inhibits the formation of aggregates/filaments of tau induced by 14-3-3. As the phosphorylation at Ser214 is up-regulated in fetal brain, tau's interaction with 14-3-3 may have a significant role in the organization of the microtubule cytoskeleton in development. Also as the phosphorylation at Ser214 is up-regulated in Alzheimer's disease brain, tau's interaction with 14-3-3 might be involved in the pathology of this disease.