Examining the zinc binding site of the amyloid-beta peptide.
The amyloid beta-peptide (Abeta) is a principal component of insoluble amyloid plaques which are characteristic neuropathological features of Alzheimer's disease. Abeta 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 Abeta-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 Abeta 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 beta-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 Abeta that involves these central histidine residues.
Yang
D S
DS
Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. ds.yang@utoronto.ca
McLaurin
J
J
Qin
K
K
Westaway
D
D
Fraser
P E
PE
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D001665:Binding Sites; D002942:Circular Dichroism; D003545:Cysteine; D006639:Histidine; D020894:Microfibrils / Q000187:drug effects / Q000648:ultrastructure; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); D006639:Histidine; D015032:Zinc; D003545:Cysteine