Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172-251) and C-terminal tail (residues 368-441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self-aggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3beta increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMP-dependent protein kinase diminished its activity (approximately 70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.

译文

微管相关蛋白tau异常过度磷酸化,聚集成阿尔茨海默氏病大脑中的神经原纤维缠结。tau的磷酸化位点主要位于富含脯氨酸 (残基172-251) 和C末端尾部 (残基368-441) 区域,这些区域位于微管结合重复序列的侧面。在这里,我们研究了在这些不同位点/区域的tau磷酸化对其刺激微管组装及其自聚集的活性的影响。我们发现,双特异性酪氨酸磷酸化和调节激酶1A在富含脯氨酸的区域的tau磷酸化适度抑制了其微管组装活性,并略微促进了其自身聚集。糖原合酶kinase-3beta在C末端尾部区域的Tau磷酸化增加了其活性并显着促进了其自聚集。cAMP依赖性蛋白激酶在两个区域加上微管结合区域的Tau磷酸化降低了其活性 (约70% 抑制) 并破坏了微管。这些研究揭示了tau的生物活性和通过在各个位置/区域的磷酸化而产生的自聚集的差异调节。

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