Identifying the minimal copper- and zinc-binding site sequence in amyloid-β 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-beta (A beta) peptides are complexed with either Cu(II) or Zn(II). Exploiting information obtained on a selected set of fragments of the A beta peptide, we identify along the sequence the histidine residues coordinated to the metal in the various peptides we have studied (A beta(1-40), A beta(1-16), A beta(1-28), A beta(5-23), and A beta(17-40)). 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 (His(6), His(13), and His(14)). In zinc-A beta 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 beta peptide sequence, this geometrical arrangement hints at a Zn(II)-promoted interpeptide aggregation mode.