title: Rapid exchange of metal between Zn(7)-metallothionein-3 and amyloid-β peptide promotes amyloid-related structural changes.
abstract: Metal ions, especially Zn(2+) and Cu(2+), are implemented in the neuropathogenesis of Alzheimer's disease (AD) by modulating the aggregation of amyloid-β peptides (Aβ). Also, Cu(2+) may promote AD neurotoxicity through production of reactive oxygen species (ROS). Impaired metal ion homeostasis is most likely the underlying cause of aberrant metal-Aβ interaction. Thus, focusing on the body's natural protective mechanisms is an attractive therapeutic strategy for AD. The metalloprotein metallothionein-3 (MT-3) prevents Cu-Aβ-mediated cytotoxicity by a Zn-Cu exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an Aβ-metal-MT-3 complex is formed. We studied the exchange of metal between Aβ and Zn(7)-MT-3 by a combination of spectroscopy (absorption, fluorescence, thioflavin T assay, and nuclear magnetic resonance) and transmission electron microscopy. We found that the metal exchange occurs via free Cu(2+) and that an Aβ-metal-MT-3 complex is not formed. This means that the metal exchange does not require specific recognition between Aβ and Zn(7)-MT-3. Also, we found that the metal exchange caused amyloid-related structural and morphological changes in the resulting Zn-Aβ aggregates. A detailed model of the metal exchange mechanism is presented. This model could potentially be important in developing therapeutics with metal-protein attenuating properties in AD.
authors.affiliation: Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
authors.forename: Jeppe T
authors.initials: JT
authors.lastname: Pedersen
authors.forename: Christelle
authors.initials: C
authors.lastname: Hureau
authors.forename: Lars
authors.initials: L
authors.lastname: Hemmingsen
authors.forename: Niels H H
authors.initials: NH
authors.lastname: Heegaard
authors.forename: Jesper
authors.initials: J
authors.lastname: Østergaard
authors.forename: Milan
authors.initials: M
authors.lastname: Vašák
authors.forename: Peter
authors.initials: P
authors.lastname: Faller
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry; D008668:Metallothionein / Q000737:chemistry* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D003300:Copper; D008668:Metallothionein; D015032:Zinc