Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

Takashi Miura, Kiyoko Suzuki, Naohito Kohata, Hideo Takeuchi

Research output: Contribution to journalArticlepeer-review

400 Citations (Scopus)


Aggregation of the amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the Aβ 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 Aβ 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- Aβ complex is correlated with the metal binding mode. Zn(II) binds to the N(τ) atom of the histidine imidazole ring and the peptide aggregates through intermolecular His(N(τ))-Zn(II)-His(N(τ)) bridges. The Nτ-metal ligation also occurs in Cu(II)-induced Aβ aggregation at mildly acidic pH. At neutral pH, however, Cu(II) binds to N(π), 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)-Aβ complexes. Under normal physiological conditions, Cu(II) is expected to protect Aβ against Zn(II)-induced aggregation by competing with Zn(II) for histidine residues of Aβ.

Original languageEnglish
Pages (from-to)7024-7031
Number of pages8
Issue number23
Publication statusPublished - 2000 Jun 13

ASJC Scopus subject areas

  • Biochemistry


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