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Examining the zinc binding site of the amyloid‐β peptide

Yang, Dun‐Sheng, McLaurin, JoAnne, Qin, Kefeng, Westaway, David, Fraser, Paul E.
European journal of biochemistry 2000 v.267 no.22 pp. 6692-6698
Alzheimer disease, amyloid, binding sites, chelation, electron microscopy, histidine, ions, peptides, zinc
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.