The structure of the amyloid-beta peptide high-affinity copper II binding site in Alzheimer disease.
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.
Streltsov
Victor A
VA
Commonwealth Scientific Industrial Research Organization Molecular and Health Technologies, and Preventative Health Flagship, Parkville, Victoria 3052, Australia. victor.streltsov@csiro.au
Titmuss
Stephen J
SJ
Epa
V Chandana
VC
Barnham
Kevin J
KJ
Masters
Colin L
CL
Varghese
Joseph N
JN
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
D016229:Amyloid beta-Peptides; D002021:Buffers; D003300:Copper