BIOL 30 |
| The amyloid beta peptide is a 39-43 residue peptide believed to be involved in the pathogenesis of Alzheimer's disease. The most common forms are Aβ(1-40) and Aβ(1-42). The former is more soluble, and the latter, prone to aggregation, is the most abundant form of Aβ found in senile plaques. Amyloid beta peptides have been shown to bind Cu2+ with a 1:1 and 2:1 Cu2+:Aβ stoiciohmetry with affinity constants (Ka) ranging in the order of 106 through 1010. In this report, we present stoichiometry and affinity data for copper binding to Aβ(1-40) and Aβ(1-16) as determined by isothermal titration calorimetry (ITC). The titration of Cu(gly)2 to Aβ(1-40) demonstrates a 1:1 stoichiometry with and Ka = 6x106 M-1 at pH 7.4 at 37 °C. Analogous results are found for Aβ(1-16) having a 1:1 Cu2+:Aβ stoichiometry and Ka = 1x107 M-1 under the same conditions. ITC also measures the enthalpy of copper binding to Aβ and was found to be ΔH ~ –8 kcal/mol and –7.5 kcal/mol for Aβ(1-40) and Aβ(1-16), respectively. The thermodynamic similarity of Cu2+ binding to Aβ(1-40) and Aβ(1-16) confirms that the copper binding occurs in the N-terminal domain and Aβ(1-16) can serve as an adequate model for the full length peptide for copper binding studies. An altered Aβ(1-16) peptide having histidine residues 6, 13, and 14, substituted to alanine residues displayed no binding to copper, indicating that at least one, or all of the histidine residues make up the Cu2+ binding site. |
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Frontiers in Chemical Biology
5:00 PM-7:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Biological Chemistry |