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Metal swap between Zn7metallothionein–3 and amyloid–β–Cu protects against amyloid–β toxicity


Meloni, G; Sonois, V; Delaine, T; Guilloreau, L; Gillet, A; Teissie, J; Faller, P; Vasak, M (2008). Metal swap between Zn7metallothionein–3 and amyloid–β–Cu protects against amyloid–β toxicity. Nature Chemical Biology, 4(6):366-372.

Abstract

Aberrant interactions of copper and zinc ions with the amyloid–β peptide (Aβ) potentiate Alzheimer 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 down–regulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Aβ. Herein, 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 in treating AD.

Abstract

Aberrant interactions of copper and zinc ions with the amyloid–β peptide (Aβ) potentiate Alzheimer 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 down–regulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Aβ. Herein, 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 in treating AD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:4 May 2008
Deposited On:24 Oct 2008 13:23
Last Modified:05 Apr 2016 12:28
Publisher:Nature Publishing Group
ISSN:1552-4450
Publisher DOI:https://doi.org/10.1038/nchembio.89
Official URL:http://www.nature.com/nchembio/journal/v4/n6/full/nchembio.89.html

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