Metal swap between Zn7-metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity
Metal swap between Zn7-metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity
复制标题
DOI：
10.1038/nchembio.89
复制
发表时间：
2008-06-01
影响因子：
14.8
通讯作者：
Vasak, Milan
中科院分区：
文献类型：
--
作者：
Meloni, Gabriele;Sonois, Vanessa;Vasak, Milan
铜离子和锌离子与淀粉样β肽 (Aβ) 的异常相互作用会参与 Ab 的聚集过程和活性氧 (ROS) 的产生，从而加剧阿尔茨海默病 (AD)。 Ab 的 ROS 产生和神经毒性与铜结合有关。金属硫蛋白-3 (Zn(7)MT-3) 是一种细胞内和细胞外存在的金属蛋白，在大脑中高表达，但在 AD 中表达下调。这种蛋白质通过一种未知的机制保护培养的神经元免受抗体的毒性。在这里，我们发现 Zn(7)MT-3 和可溶性聚集的 A beta(1-40)-Cu(II) 之间的金属交换消除了 ROS 的产生和相关的细胞毒性。在此过程中，铜被蛋白质硫醇盐还原，形成 Cu(I)(4)Zn(4)MT-3，其中存在空气稳定的 Cu(I)(4)-硫醇盐簇和两个二硫键。已发现的 Zn(7)MT-3 对铜介导的 A beta(1-40) 毒性的保护作用可能会导致治疗 AD 的新治疗策略。
Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (A beta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Ab and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Ab are associated with copper binding. Metallothionein-3 (Zn(7)MT-3), an intra- and extracellularly occurring metalloprotein, is highly expressed in the brain and downregulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Ab. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated A beta(1-40)-Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air-stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn(7)MT-3 from the copper-mediated A beta(1-40) toxicity may lead to new therapeutic strategies for treating AD.