Quantification of the Binding Properties of Cu2+ to the Amyloid Beta Peptide: Coordination Spheres for Human and Rat Peptides and Implication on Cu2+-Induced Aggregation
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2010
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There is no consensus on the coordinating ligands for Cu2+ by A beta. However, the differences in peptide sequence between human and rat have been hypothesized to alter metal ion binding in a manner that alters Cu2+-induced aggregation of A beta. Herein, we employ isothermal titration calorimetry (ITC), circular dichroism (CD), and electron paramagnetic resonance (EPR) spectroscopy to examine the Cu2+ coordination spheres to human and rat A beta and an extensive set of A beta(16) mutants. EPR of the mutant peptides is consistent with a 3N1O binding geometry, like the native human peptide at pH 7.4. The thermodynamic data reveal an equilibrium between three coordination spheres, {NH2, O, NIm(His6), N-}, {NH2, O, N-Im(His6), N-Im(His13)}, and {NH2, O, N-Im(His6), N-Im(His14)}, for human A beta(16) but one dominant coordination for rat A beta(16), {NH2, O, N-Im(His6), N-}, at pH 7.4-6.5. ITC and CD data establish that the mutation R5G is sufficient for reproducing this difference in Cu2+ binding properties at pH 7.4. The substitution of bulky and positively charged Arg by Gly is proposed to stabilize the coordination {NH2, O-, NIm(His6), N-} that then results in one dominating coordination sphere for the case of the rat peptide. The differences in the coordination geometries for Cu2+ by the human and rat A beta are proposed to contribute to the variation in the ability of Cu2+ to induce aggregation of A beta peptides.
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