title: The structure of the amyloid-beta peptide high-affinity copper II binding site in Alzheimer disease.
abstract: Neurodegeneration observed in Alzheimer disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the amyloid-beta (Abeta) protein bound primarily to copper ions. The evidence for an oxidative stress role of Abeta-Cu redox chemistry is still incomplete. Details of the copper binding site in Abeta may be critical to the etiology of AD. Here we present the structure determined by combining x-ray absorption spectroscopy (XAS) and density functional theory analysis of Abeta peptides complexed with Cu(2+) in solution under a range of buffer conditions. Phosphate-buffered saline buffer salt (NaCl) concentration does not affect the high-affinity copper binding mode but alters the second coordination sphere. The XAS spectra for truncated and full-length Abeta-Cu(2+) peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the Abeta-Cu(2+) complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu(2+) binding site is consistent with the hypothesis that the redox activity of the metal ion bound to Abeta can lead to the formation of dityrosine-linked dimers found in AD.
authors.affiliation: Commonwealth Scientific Industrial Research Organization Molecular and Health Technologies, and Preventative Health Flagship, Parkville, Victoria 3052, Australia. victor.streltsov@csiro.au
authors.forename: Victor A
authors.initials: VA
authors.lastname: Streltsov
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Titmuss
authors.forename: V Chandana
authors.initials: VC
authors.lastname: Epa
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Varghese
mesh_terms: D000042:Absorption; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002021:Buffers; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D013696:Temperature; D014965:X-Rays
chemical_list: D016229:Amyloid beta-Peptides; D002021:Buffers; D003300:Copper