Characterization of the Zn super(II) Binding to the Peptide Amyloid- beta super(1-16) linked to Alzheimer's Disease

Aggregation of the human peptide amyloid- beta (A beta ) is a key event in Alzheimer's disease (AD). Zinc ions play an important role in AD and in A beta aggregation. In vitro, Zn super(II) binds to A beta and accelerates its aggregation. In this work we have investigated Zn super(II) binding to the synthetic peptide A beta super(1-16), which contains the metal-binding domain of A beta . Cd super(II) was used to probe the Zn super(II) site. A beta super(1-16) bound one equivalent of Zn super(II) with an apparent dissociation constant (K sub(d)) of 10 super(- 4) M. This K sub(d) value is in the same range as the Zn concentration needed to precipitate A beta . Circular dichroism and NMR indicated predominantly random- coil secondary structures of apo-A beta super(1-16), Zn super(II)-A beta super(1-16) and Cd super(II)-A beta super(1-16), which were all highly dynamic and flexible. The three histidines at positions 6, 13 and 14 were suggested to be ligands to Zn super(II) and Cd super(II). Evidence that the aspartate at position 1 served as a fourth ligand to Zn super(II) and Cd super(II) was found at pH 8.7. super(111)Cd super(II) NMR showed a resonance at 84 ppm, in line with a mixed oxygen-/nitrogen-ligand environment. The tyrosine at position 10 could be excluded as a ligand.