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Article
Nature Chemical Biology 4, 366–372 (1 June 2008) | doi:10.1038/nchembio.89
Metal swap between Zn7-metallothionein-3 and amyloid-|[beta]||[ndash]|Cu protects against amyloid-|[beta]| toxicity
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Abstract
Aberrant interactions of copper and zinc ions with the amyloid-β peptide (Aβ) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Aβ and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Aβ are associated with copper binding. Metallothionein-3 (Zn7MT-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 Aβ. Here, we show that a metal swap between Zn7MT-3 and soluble and aggregated Aβ1–40–Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)4Zn4MT-3, in which an air-stable Cu(I)4-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn7MT-3 from the copper-mediated Aβ1–40 toxicity may lead to new therapeutic strategies for treating AD.
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