Identifying the Minimal Copper- and Zinc-binding Site Sequence in Amyloid-beta Peptides

With a combination of complementary experimental techniques, namely sedimentation assay, Fourier transform infrared spectroscopy, and x-ray absorption spectroscopy, we are able to determine the atomic structure around the metal-binding site in samples where amyloid- (A) peptides are complexed with either Cu(II) or Zn(II). Exploiting information obtained on a selected set of fragments of theA peptide, we identify along the sequence the histidine residues coordinated to the metal in the various peptides we have studied (A1–40,A1–16,A1–28,A5–23, and A17–40). Our data can be consistently interpreted assuming that all of the peptides encompassing the minimal 1–16 amino acidic sequence display a copper coordination mode that involves three histidines (His6, His13, and His14). In zinc-A complexes, despite the fact that the metal coordination appears to be more sensitive to solution condition and shows a less rigid geometry around the binding site, a four-histidine coordination mode is seen to be preferred. Lacking a fourth histidine along the A peptide sequence, this geometrical arrangement hints at a Zn(II)-promoted interpeptide aggregation mode.