Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes.
Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the Abeta aggregation at acidic-to-neutral pH, while Cu(II) is an effective inducer only at mildly acidic pH. We have examined Zn(II) and Cu(II) binding modes of Abeta and their pH dependence by Raman spectroscopy. The Raman spectra clearly demonstrate that three histidine residues in the N-terminal hydrophilic region provide primary metal binding sites and the solubility of the metal-Abeta complex is correlated with the metal binding mode. Zn(II) binds to the N(tau) atom of the histidine imidazole ring and the peptide aggregates through intermolecular His(N(tau))-Zn(II)-His(N(tau)) bridges. The N(tau)-metal ligation also occurs in Cu(II)-induced Abeta aggregation at mildly acidic pH. At neutral pH, however, Cu(II) binds to N(pi), the other nitrogen of the histidine imidazole ring, and to deprotonated amide nitrogens of the peptide main chain. The chelation of Cu(II) by histidine and main-chain amide groups results in soluble Cu(II)-Abeta complexes. Under normal physiological conditions, Cu(II) is expected to protect Abeta against Zn(II)-induced aggregation by competing with Zn(II) for histidine residues of Abeta.
Miura
T
T
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan.
Suzuki
K
K
Kohata
N
N
Takeuchi
H
H
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D003300:Copper / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D012995:Solubility; D013059:Spectrum Analysis, Raman; D015032:Zinc / Q000737:chemistry
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D006639:Histidine; D003300:Copper; D015032:Zinc