The amyloid β‐peptide (Aβ) is a principal component of insoluble amyloid plaques which are characteristic neuropathological features of Alzheimer's disease. Aβ also exists as a normal soluble protein that undergoes a pathogenic transition to an aggregated, fibrous form. This transition can be affected by extraneous proteinaceous and nonproteinaceous elements, such as zinc ions, which may promote aggregation and/or stabilization of the fibrils. Protein chelation of zinc is typically mediated by histidines, cysteines and carboxylates. Previous studies have demonstrated that the Aβ‐Zn2+ binding site is localized within residues 6–28 and that histidines may serve as the principal sites of interaction. To localize key residues within this region, a series of Aβ peptides (residues 1–28) were synthesized that contained systematic His/Ala substitutions. Circular dichroism and electron microscopy were used to monitor the effects of Zn2+ on the peptide β‐sheet conformation and fibril aggregation. Our results indicate that substitution of either His13 or His14 but not His6 eliminates the zinc‐mediated effects. These observations indicate a specific zinc binding site within Aβ that involves these central histidine residues.

Yang, D., McLaurin, J., Qin, K., Westaway, D., & Fraser, P. E. (2000). Examining the zinc binding site of the amyloid‐β peptide. European Journal of Biochemistry, 267(22), 6692–6698. Portico.