Solution 1H NMR investigation of Zn2+ and Cd2+ binding to amyloid-beta peptide (Aβ) of Alzheimer's disease
✍ Scribed by Christopher D. Syme; John H. Viles
- Publisher
- Elsevier Science
- Year
- 2006
- Tongue
- English
- Weight
- 618 KB
- Volume
- 1764
- Category
- Article
- ISSN
- 1570-9639
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✦ Synopsis
Elevated levels of zinc 2+ and copper 2+ are found chelated to the amyloid-beta-peptide (Ah) in isolated senile plaque cores of Alzheimer's disease (AD) patients. However, the precise residues involved in Zn 2+ ligation are yet to be established. We have used 1 H NMR and CD to probe the binding of Zn 2+ to Ah(1 -28). Zinc binding to Ah causes a number of 1 H NMR resonances to exhibit intermediate exchange broadening upon Zn 2+ addition, signals in slow and fast exchange are also observed. In addition, there is a general loss of signal for all resonances with Zn 2+ addition, suggestive of the formation of high molecular weight polymeric species. Perturbations in specific 1 H NMR resonances between residues 6 and 14, and analysis of various Ah analogues in which each of the three His residues have been replaced by alanine, indicates that His6, His13 and His14 residues are implicated in Zn-Ah binding. Complementary studies with Cd 2+ ions cause perturbations to 1 H NMR spectra that are strikingly similar to that observed for Zn 2+ . Binding monitored at Val12 indicates a 1:1 stoichiometry with Ah for both Zn 2+ and Cd 2+ ions. Circular Dichroism (CD) studies in the far-UV indicate quite minimal ordering of the main-chain with Zn 2+ or Cd 2+ addition. Changes in the far-UV are quite different from that obtained with Cu 2+ additions indicating that Zn 2+ coordination is distinct from that of Cu 2+ ions. Taken together, these observations seem to suggest that Zn 2+ coordination is dominated by inter-molecular coordination and the formation of polymeric species.