Metal swap between Zn7-metallothionein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity.
Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (Abeta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Abeta and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Abeta 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 Abeta. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated Abeta(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 Abeta(1-40) toxicity may lead to new therapeutic strategies for treating AD.
Meloni
Gabriele
G
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Sonois
Vanessa
V
Delaine
Tamara
T
Guilloreau
Luc
L
Gillet
Audrey
A
Teissié
Justin
J
Faller
Peter
P
Vasák
Milan
M
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008668:Metallothionein / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009942:Organometallic Compounds / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000737:chemistry
D016229:Amyloid beta-Peptides; D009942:Organometallic Compounds; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D003300:Copper; D008668:Metallothionein; D015032:Zinc