Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1764, Issue 2, Pages 246-256Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbapap.2005.09.012
Keywords
zinc; spectroscopy; structure; CD; aggregation
Categories
Funding
- BBSRC [BB/D005027/1] Funding Source: UKRI
- MRC [MC_U117533887] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D005027/1] Funding Source: researchfish
- Medical Research Council [MC_U117533887] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/D005027/1] Funding Source: Medline
- Medical Research Council [MC_U117533887] Funding Source: Medline
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Elevated levels of zinc(2+) and copper(2+) are found chelated to the amyloid-beta-peptide (A beta) in isolated senile plaque cores of Alzheimer's disease (AD) patients. However, the precise residues involved in Zn2+ ligation are yet to be established. We have used H-1 NMR and CD to probe the binding of Zn2+ to A beta(1-28). Zinc binding to A beta causes a number of H-1 NMR resonances to exhibit intermediate exchange broadening upon Zn2+ addition, signals in slow and fast exchange are also observed. In addition, there is a general loss of signal for all resonances with Zn2+ addition, suggestive of the formation of high molecular weight polymeric species. Perturbations in specific H-1 NMR resonances between residues 6 and 14, and analysis of various A beta analogues in which each of the three His residues have been replaced by alanine, indicates that His6, His 13 and His14 residues are implicated in Zn-A beta binding. Complementary studies with Cd2+ ions cause perturbations to 1H NMR spectra that are strikingly similar to that observed for Zn2+. Binding monitored at Val12 indicates a 1:1 stoichiometry with A for both Zn2+ and Cd2+ ions. Circular Dichroism. (CD) studies in the far-UV indicate quite minimal ordering of the main-chain with Zn2+ or Cd2+ addition. Changes in the far-UV are quite different from that obtained with Cu2+ additions indicating that Zn2+ coordination is distinct from that Of Cu2+ ions. Taken together, these observations seem to suggest that Zn2+ coordination is dominated by inter-molecular coordination and the formation of polymeric species. (c) 2005 Elsevier B.V All rights reserved.
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