Rapid Exchange of Metal between Zn7鈥揗etallothionein-3 and Amyloid-尾 Peptide Promotes Amyloid-Related Structural Changes

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• 作者：Jeppe T. Pedersen ; Christelle Hureau ; Lars Hemmingsen ; Niels H. H. Heegaard ; Jesper 脴stergaard ; Milan Va拧谩k ; Peter Faller
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：February 28, 2012
• 年：2012
• 卷：51
• 期：8
• 页码：1697-1706
• 全文大小：418K
• 年卷期：v.51,no.8(February 28, 2012)
• ISSN：1520-4995

文摘

Metal ions, especially Zn²⁺ and Cu²⁺, are implemented in the neuropathogenesis of Alzheimer鈥檚 disease (AD) by modulating the aggregation of amyloid-尾 peptides (A尾). Also, Cu²⁺ may promote AD neurotoxicity through production of reactive oxygen species (ROS). Impaired metal ion homeostasis is most likely the underlying cause of aberrant metal鈥揂尾 interaction. Thus, focusing on the body鈥檚 natural protective mechanisms is an attractive therapeutic strategy for AD. The metalloprotein metallothionein-3 (MT-3) prevents Cu鈥揂尾-mediated cytotoxicity by a Zn鈥揅u exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an A尾鈥搈etal鈥揗T-3 complex is formed. We studied the exchange of metal between A尾 and Zn₇鈥揗T-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 Cu²⁺ and that an A尾鈥搈etal鈥揗T-3 complex is not formed. This means that the metal exchange does not require specific recognition between A尾 and Zn₇鈥揗T-3. Also, we found that the metal exchange caused amyloid-related structural and morphological changes in the resulting Zn鈥揂尾 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.