Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3

Metal ions have been suggested to induce aggregation of amyloid β-peptide (Aβ), 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 Aβ fragment, which exhibits a clear-cut dependence on the amino acid sequence. A heptapeptide, EFRHDSG, corresponding to the amino acid residues 3-9 of Aβ (Aβ_3-9) undergoes a conformational transition from irregular to β-sheet and self-associates into insoluble aggregates upon Cu(II) binding. A Raman spectrum analysis of the Cu(II)-Aβ_3-9 complex and aggregation assays of mutated Aβ_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 Aβ_1-9 and Aβ_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).