NMR Studies of Zinc, Copper, and Iron Binding to Histidine, the Principal Metal Ion Complexing Site of Amyloid-β Peptide

Amyloid-alpha (A beta), the major component of senile plaques in Alzheimer's disease, is known to complex transition metal ions mainly through histidine residues. In this study, using (1)H NMR titration experiments, we show that histidine binds strongly to Zn(II), Cu(II), and Fe(III) ions at a biologically relevant pH (pH 7.4), with a stoichiometry of Zn(II): histidine binding of 1:2. The observed deshielding of the chemical shifts and relative line broadening indicate that Fenton-active Cu(II) and Fe(III) bind to histidine relatively more efficiently as compared to Zn(II). Parallel studies showed that glutamic acid and aspartic acid are relatively inefficient in metal ion binding. From these studies, we suggest that A beta-chelated Zn(II) is readily displaced by Cu(II) and Fe(III) ions and leads to a propagation of oxidative stress.