Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation
Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation
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DOI：
10.1111/j.1460-9568.2007.05955.x
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发表时间：
2007-12-01
影响因子：
3.4
通讯作者：
Gong, Cheng-Xin
中科院分区：
文献类型：
--
作者：
Liu, Fei;Li, Bin;Gong, Cheng-Xin
在阿尔茨海默病患者的大脑中，微管相关蛋白tau异常过度磷酸化并聚集成神经原纤维缠结。tau蛋白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tau富含脯氨酸区域的磷酸化适度抑制了其微管组装活性，并略微促进了其自聚集。糖原合成酶激酶-3 β在c端尾区磷酸化Tau蛋白，使其活性增加，并显著促进其自聚集。camp依赖性蛋白激酶在这两个区域和微管结合区域的Tau磷酸化降低了其活性（类似于70%的抑制）并破坏了微管。这些研究揭示了不同位点/区域的磷酸化对tau的生物活性和自聚集的差异调节。
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-3 beta 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 (similar to 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.