Identifying the minimal copper- and zinc-binding site sequence in amyloid-β peptides

Abstract

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-β (Aβ) peptides are complexed with either Cu(II) or Zn(II). Exploiting information obtained on a selected set of fragments of the Aβ peptide, we identify along the sequence the histidine residues coordinated to the metal in the various peptides we have studied (Aβ1-40, Aβ1-16, Aβ 1-28, Aβ5-23, and Aβ17-40). 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 His 14). In zinc-Aβ 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 Aβ peptide sequence, this geometrical arrangement hints at a Zn(II)-promoted interpeptide aggregation mode. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.