Web Release Date: June 30,
Histidine-13 Is a Crucial Residue in the Zinc Ion-Induced Aggregation of the A
Peptide of Alzheimer's Disease
and
School of Chemistry and Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3052, Australia
Received January 27, 1999
Revised Manuscript Received April 7, 1999
Abstract:
Metal ions such as Zn2+ and Cu2+ have been implicated in both the aggregation and
neurotoxicity of the -amyloid (A) peptide that is present in the brains of Alzheimer's sufferers. Zinc
ions in particular have been shown to induce rapid aggregation of A. Rat A binds zinc ions much less
avidly than human A, and rats do not form cerebral A amyloid. Rat A differs from human A by the
substitution of Gly for Arg, Phe for Tyr, and Arg for His at positions 5, 10, and 13, respectively. Through
the use of synthetic peptides corresponding to the first 28 residues of human A, rat A, and single-residue variations, we use circular dichroism spectroscopy, sedimentation assays, and immobilized metal
ion affinity chromatography to show that the substitution of Arg for His-13 is responsible for the different
Zn2+-induced aggregation behavior of rat and human A. The coordination of Zn2+ to histidine-13 is
critical to the zinc ion induced aggregation of A.
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