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Author Notes:

Corresponding Author: Kurt Warncke Department of Physics N201 Mathematics and Science Center 400 Dowman Drive Emory University Atlanta, Georgia 30322-2430 kwarncke@physics.emory.edu Phone: 404-727-2975 Fax: 404-727-0873


Research Funding:

The purchase of the Bruker E500 EPR spectrometer was funded by NIH NCRR grant RR17767 and by Emory University.

Local Structure and Global Patterning of Cu2+ Binding in Fibrillar Amyloid-β [Aβ(1-40)] Protein


Journal Title:

Journal of the American Chemical Society


Volume 134, Number 44


, Pages 18330-18337

Type of Work:

Article | Post-print: After Peer Review


The amyloid-β (Aβ) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu2+, is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high-resolution pulsed-electron paramagnetic resonance (EPR) spectroscopy to characterize the coordination structure of Cu2+ in the fibrillar form of full-length Aβ(1-40). The results reveal a bis-cis-histidine (His) equatorial Cu2+ coordination geometry, and participation of all three N-terminal His residues in Cu2+ binding. A model is proposed, in which Cu2+–His6/His13 and Cu2+–His6/His14 sites alternate along the fibril axis, on opposite sides of the β-sheet fibril structure. The local intra-β-strand coordination structure is not conducive to Cu2+/Cu1+ redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multi-electron and bridged-metal site reactivity. This indicates that the fibrillar form of Aβ suppresses Cu redox cycling and reactive oxygen species (ROS) production. The insulator configuration suggests application of Cu2+-Aβ fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity.

Copyright information:

© 2012 American Chemical Society

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