Format

Send to

Choose Destination
Biophys J. 2008 Oct;95(7):3447-56. doi: 10.1529/biophysj.108.134429. Epub 2008 Jul 3.

The structure of the amyloid-beta peptide high-affinity copper II binding site in Alzheimer disease.

Author information

1
Commonwealth Scientific Industrial Research Organization Molecular and Health Technologies, and Preventative Health Flagship, Parkville, Victoria 3052, Australia. victor.streltsov@csiro.au

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.

PMID:
18599641
PMCID:
PMC2547438
DOI:
10.1529/biophysj.108.134429
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center