Article abstract
Nature Chemical Biology 4, 366 - 372 (2008)
Published online: 4 May 2008 | doi:10.1038/nchembio.89
Metal swap between Zn7-metallothionein-3 and amyloid-
–Cu protects against amyloid- toxicity
Gabriele Meloni1,
Vanessa Sonois2,3,
Tamara Delaine2,
Luc Guilloreau2,
Audrey Gillet2,
Justin Teissié3,
Peter Faller2
&
Milan Va
ák1
Abstract
Aberrant interactions of copper and zinc ions with the amyloid-
peptide (A) potentiate Alzheimer's disease (AD) by participating in the aggregation process of A and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of A 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 A. Here, we show that a metal swap between Zn7MT-3 and soluble and aggregated A1–40–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 A1–40 toxicity may lead to new therapeutic strategies for treating AD.
- Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
- Laboratoire de Chimie de Coordination, 205 route de Narbonne, 31077 Toulouse Cedex, France.
- Institut de Pharmacologie et Biologie Structurale, 205 route de Narbonne, 31077 Toulouse Cedex, France.
Correspondence to: Milan Vaák1
e-mail: mvasak@bioc.uzh.ch
Correspondence to: Peter Faller2 e-mail: peter.faller@lcc-toulouse.fr
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