Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322
Low Micromolar Zinc Accelerates the Fibrillization of Human Tau via Bridging of Cys-291 and Cys-322
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低微摩尔锌通过桥接 Cys-291 和 Cys-322 加速人 Tau 纤维化
DOI：
10.1074/jbc.m109.058883
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Liang, Yi
中科院分区：
文献类型：
--
作者：
Mo, Zhong-Ying;Zhu, Ying-Zhu;Liang, Yi
阿尔茨海默病等一组神经退行性疾病的一个标志是神经原纤维缠结的形成，神经原纤维缠结主要由微管相关蛋白 Tau 形成的丝束组成。阐明天然非结构化 Tau 蛋白如何形成异常聚集体对于阐明这些疾病的病因至关重要。有大量证据表明，锌作为一种高度集中在大脑中的必需元素，与这些疾病的发生或进展有关。在此，我们利用重组人Tau片段Tau(244-372)及其突变体，研究了锌对Tau聚集的影响。与无 Zn2+ 相比，低微摩尔浓度的 Zn2+ 在还原条件下可显着加速野生型 Tau(244-372) 的原纤维形成。然而，较高浓度的 Zn2+ 会诱导野生型 Tau(244-372) 在还原条件下形成颗粒状聚集体。此外，当 Zn2+ 被 EDTA 螯合时，这些非纤维状聚集体组装成成熟的 Tau 丝。与野生型Tau(244-372)不同，低微摩尔浓度的Zn2+对还原条件下单突变体C291A和C322A以及双突变体C291A/C322A的纤维化动力学没有明显影响。等温滴定量热法的结果表明，1 个 Zn2+ 通过与 Cys-291 和 Cys-322 以及两个组氨酸的四面体配位与一个 Tau 分子结合，具有中等的微摩尔亲和力。我们的数据表明，低微摩尔锌在生理还原条件下通过桥接 Cys-291 和 Cys-322 加速人 Tau 蛋白的纤维化，为了解锌动态平衡失调与神经退行性疾病病因之间的关系提供线索。
A hallmark of a group of neurodegenerative diseases such as Alzheimer disease is the formation of neurofibrillary tangles, which are principally composed of bundles of filaments formed by microtubule-associated protein Tau. Clarifying how natively unstructured Tau protein forms abnormal aggregates is of central importance for elucidating the etiology of these diseases. There is considerable evidence showing that zinc, as an essential element that is highly concentrated in brain, is linked to the development or progression of these diseases. Herein, by using recombinant human Tau fragment Tau(244-372) and its mutants, we have investigated the effect of zinc on the aggregation of Tau. Low micromolar concentrations of Zn2+ dramatically accelerate fibril formation of wild-type Tau(244-372) under reducing conditions, compared with no Zn2+. Higher concentrations of Zn2+, however, induce wild-type Tau(244-372) to form granular aggregates in reducing conditions. Moreover, these non-fibrillar aggregates assemble into mature Tau filaments when Zn2+ has been chelated by EDTA. Unlike wild-type Tau(244-372), low micromolar concentrations of Zn2+ have no obvious effects on fibrillization kinetics of single mutants C291A and C322A and double mutant C291A/C322A under reducing conditions. The results from isothermal titration calorimetry show that one Zn2+ binds to one Tau molecule via tetrahedral coordination to Cys-291 and Cys-322 as well as two histidines, with moderate, micromolar affinity. Our data demonstrate that low micromolar zinc accelerates the fibrillization of human Tau protein via bridging Cys-291 and Cys-322 in physiological reducing conditions, providing clues to understanding the relationship between zinc dyshomeostasis and the etiology of neurodegenerative diseases.