title: Local structure and global patterning of Cu2+ binding in fibrillar amyloid-β [Aβ(1-40)] protein.
abstract: The amyloid-β (Aβ) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu(2+), is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high-resolution pulsed electron paramagnetic resonance spectroscopy to characterize the coordination structure of Cu(2+) in the fibrillar form of full-length Aβ(1-40). The results reveal a bis-cis-histidine (His) equatorial Cu(2+) coordination geometry and participation of all three N-terminal His residues in Cu(2+) binding. A model is proposed in which Cu(2+)-His6/His13 and Cu(2+)-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 Cu(2+)/Cu(+) redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multielectron and bridged-metal site reactivity. This indicates that the fibrillar form of Aβ suppresses Cu redox cycling and reactive oxygen species production. The configuration suggests application of Cu(2+)-Aβ fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity.
authors.affiliation: Department of Physics, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gunderson
authors.forename: Jessica
authors.initials: J
authors.lastname: Hernández-Guzmán
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Karr
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Veronika A
authors.initials: VA
authors.lastname: Szalai
authors.forename: Kurt
authors.initials: K
authors.lastname: Warncke
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D003300:Copper / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D006639:Histidine; D003300:Copper