title: pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-β peptide.
abstract: Metal ions like Cu(II) and Zn(II) are accumulated in Alzheimer's disease amyloid plaques. The amyloid-β (Aβ) peptide involved in the disease interacts with these metal ions at neutral pH via ligands provided by the N-terminal histidines and the N-terminus. The present study uses high-resolution NMR spectroscopy to monitor the residue-specific interactions of Cu(II) and Zn(II) with (15)N- and (13)C,(15)N-labeled Aβ(1-40) peptides at varying pH levels. At pH 7.4 both ions bind to the specific ligands, competing with one another. At pH 5.5 Cu(II) retains its specific histidine ligands, while Zn(II) seems to lack residue-specific interactions. The low pH mimics acidosis which is linked to inflammatory processes in vivo. The results suggest that the cell toxic effects of redox active Cu(II) binding to Aβ may be reversed by the protective activity of non-redox active Zn(II) binding to the same major binding site under non-acidic conditions. Under acidic conditions, the protective effect of Zn(II) may be decreased or changed, since Zn(II) is less able to compete with Cu(II) for the specific binding site on the Aβ peptide under these conditions.
authors.affiliation: Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden. leila.ghalebani@ki.se
authors.forename: Leila
authors.initials: L
authors.lastname: Ghalebani
authors.forename: Anna
authors.initials: A
authors.lastname: Wahlström
authors.forename: Jens
authors.initials: J
authors.lastname: Danielsson
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D003300:Copper; D015032:Zinc