The Structure of the Amyloid-[beta] Peptide High-Affinity Copper II Binding Site in Alzheimer Disease

Journal Article · Mon Nov 03 04:00:00 EST 2008 · Biochem. Biophys. Res. Commun.

DOI:https://doi.org/10.1529/biophysj.108.134429· OSTI ID:1006914

Streltsov, Victor A; Titmuss, Stephen J; Epa, V Chandana; Barnham, Kevin J; Masters, Colin L; Varghese, Joseph N ^[1]

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1. CSIRO/MHT

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} (A{beta}) protein bound primarily to copper ions. The evidence for an oxidative stress role of A{beta}-Cu redox chemistry is still incomplete. Details of the copper binding site in A{beta} 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 A{beta} peptides complexed with Cu{sup 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 A{beta}-Cu{sup 2+} peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the A{beta}-Cu{sup 2+} complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu{sup 2+} binding site is consistent with the hypothesis that the redox activity of the metal ion bound to A{beta} can lead to the formation of dityrosine-linked dimers found in AD.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1006914
• Journal Information: Biochem. Biophys. Res. Commun., Journal Name: Biochem. Biophys. Res. Commun. Journal Issue: 2008 Vol. 95; ISSN 0006-3495; ISSN BIOJAU
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
74 ATOMIC AND MOLECULAR PHYSICS
ABSORPTION SPECTROSCOPY
ASPARTIC ACID
BRAIN
BUFFERS
CHEMISTRY
COMPLEXES
COPPER
COPPER IONS
DENSITY
DENSITY FUNCTIONAL METHOD
DIMERS
DISEASES
ETIOLOGY
FUNCTIONALS
GEOMETRY
HYPOTHESIS
IONS
MENTAL DISORDERS
METALS
NERVE CELLS
NERVOUS SYSTEM DISEASES
OXYGEN
PEPTIDES
PROTEINS
SALTS
SOLUTIONS
SPECTRA
TOXICITY
WATER