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Amyloid-β Binds Cu 2+ in a Mononuclear Metal Ion Binding Site

2004; American Chemical Society; Volume: 126; Issue: 41 Linguagem: Inglês

10.1021/ja0488028

1943-2984

Jesse W. Karr, Lauren J. Kaupp, Veronika A. Szalai,

Molecular Sensors and Ion Detection

Amyloid-β (Aβ) peptide is the principal constituent of plaques associated with Alzheimer's disease and is thought to be responsible for the neurotoxicity associated with the disease. Metal ions have been hypothesized to play a role in the formation and neurotoxicity of aggregates associated with Alzheimer's disease (Bush, A. I.; et al. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11934). Elucidation of the chemistry through which transition-metal ions participate in the assembly and toxicity of Aβ oligomers is important to drug design efforts if inhibition of Aβ containing bound metal ions becomes a treatment for Alzheimer's disease. In this paper, we report electron paramagnetic resonance (EPR) spectroscopic characterization of Cu2+ bound to soluble and fibrillar Aβ. Addition of stoichiometric amounts of Cu2+ to soluble Aβ produces an EPR signal at 10 K with observable Cu2+ hyperfine lines. A nearly identical spectrum is observed for Aβ fibrils assembled in the presence of Cu2+. The EPR parameters are consistent with a Type 2 Cu2+ center with three nitrogen donor atoms and one oxygen donor atom in the coordination sphere of Cu2+: g∥ = 2.26 and A∥ = 174 ± 4 G for soluble Aβ with Cu2+, and g∥ = 2.26 and A∥ = 175 ± 1 G for Aβ fibrils assembled with Cu2+. Investigation of the temperature dependence of the EPR signal for Cu2+ bound to soluble Aβ or Cu2+ in fibrillar Aβ shows that the Cu2+ center displays normal Curie behavior, indicating that the site is a mononuclear Cu2+ site. Fibrils assembled in the presence of Cu2+ contain one Cu2+ ion per peptide. These results show that the ligand donor atom set to Cu2+ does not change during organization of Aβ monomers into fibrils and that neither soluble nor fibrillar forms of Aβ(1−40) with Cu2+ contain antiferromagnetically exchange-coupled binuclear Cu2+ sites in which two Cu2+ ions are bridged by an intervening ligand.