Abstract
The aggregation of the peptide amyloid-β (Aβ) to form amyloid plaques is a key event in Alzheimer’s disease. It has been shown that CuII can bind to soluble Aβ and influence its aggregation properties. Three histidines and the N-terminal amine have been proposed to be involved in its coordination. Here, for the first time, we show isothermal titration calorimetry (ITC) measurements of the CuII binding to Aβ16 and Aβ28, models of the soluble Aβ. Moreover, different spectroscopic methods were applied. The studies revealed new insights into these CuII–Aβ complexes: (1) ITC showed two CuII binding sites, with an apparent Kd of 10−7 and 10−5 M, respectively; (2) the high-affinity site has a smaller enthalpic contribution but a larger entropic contribution than the low-affinity binding site; (3) azide did not bind to CuII in the higher-affinity binding site, suggesting the absence of a weak, labile ligand; (4) azide could bind to the CuII in the low-affinity binding site in Aβ28 but not in Aβ16; (5) 1H-NMR suggests that the carboxylate of aspartic acid in position 1 is involved in the ligation to CuII in the high-affinity binding site; (6) the pKa of 11.3 of tyrosine in position 10 was not influenced by the binding of 2 equivalents of CuII.
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Abbreviations
- Aβ:
-
Amyloid-β
- Aβ16:
-
Amyloid-β1−16
- Aβ28:
-
Amyloid-β1-28
- AD:
-
Alzheimer’s disease
- APP:
-
Amyloid-precursor protein
- EPR:
-
Electron paramagnetic resonance
- HEPES:
-
2-(4-(2-Hydroxyethyl)-1-piperazinyl)ethanesulfonic acid
- ITC:
-
Isothermal titration calorimetry
- NOESY:
-
Nuclear Overhauser enhancement spectroscopy
- TOCSY:
-
Total correlation spectroscopy
- Tris:
-
Tris(hydroxymethyl)aminomethane
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Acknowledgements
We would like to thank A. Mari (LCC Toulouse) for EPR measurements, the research groups of B. Meunier (LCC Toulouse) and D. Fournier (IPBS, Toulouse) for access to their equipment, and P. Dorlet (ICMMO, Orsay) and C. Hureau (CEA, Saclay) for helpful discussions. The thesis of L.G. was supported by the European Social Founds.
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Guilloreau, L., Damian, L., Coppel, Y. et al. Structural and thermodynamical properties of CuII amyloid-β16/28 complexes associated with Alzheimer’s disease. J Biol Inorg Chem 11, 1024–1038 (2006). https://doi.org/10.1007/s00775-006-0154-1
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DOI: https://doi.org/10.1007/s00775-006-0154-1