Copper selectively triggers beta-sheet assembly of an N-terminally truncated amyloid beta-peptide beginning with Glu3.
Metal ions have been suggested to induce aggregation of amyloid beta-peptide (Abeta), which is a key event in Alzheimer's disease. However, direct evidence that specific metal-peptide interactions are responsible for the amyloid formation has not previously been provided. Here we present the first example of the metal-induced amyloid formation by an Abeta fragment, which exhibits a clear-cut dependence on the amino acid sequence. A heptapeptide, EFRHDSG, corresponding to the amino acid residues 3-9 of Abeta (Abeta(3-9)) undergoes a conformational transition from irregular to beta-sheet and self-associates into insoluble aggregates upon Cu(II) binding. A Raman spectrum analysis of the Cu(II)-Abeta(3-9) complex and aggregation assays of mutated Abeta(3-9) peptides demonstrated that a concerted Cu(II) coordination of the imidazole side chain of His6, the carboxyl groups of Glu3 and Asp7, and the amino group at the N-terminus is essential for the amyloid formation. Although Abeta(1-9) and Abeta(2-9) also contain the metal binding sites, neither of these peptides forms amyloid depositions in the presence of Cu(II). The results of this study may not only provide new insight into the mechanism of amyloid formation, but also be important as a step toward the construction of proteinaceous materials with a specific function under the control of Cu(II).
Miura
Takashi
T
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan. tmiura@mail.pharm.tohoku.ac.jp
Mitani
Sayoko
S
Takanashi
Chiho
C
Mochizuki
Nobuhiro
N
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D013059:Spectrum Analysis, Raman
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018698:Glutamic Acid; D003300:Copper