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JBIC Journal of Biological Inorganic Chemistry

, Volume 11, Issue 8, pp 1024–1038 | Cite as

Structural and thermodynamical properties of CuII amyloid-β16/28 complexes associated with Alzheimer’s disease

  • Luc Guilloreau
  • Luminita Damian
  • Yannick Coppel
  • Honoré Mazarguil
  • Mathias Winterhalter
  • Peter Faller
Original Paper

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 K d 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 pK a of 11.3 of tyrosine in position 10 was not influenced by the binding of 2 equivalents of CuII.

Keywords

Copper β-amyloid Calorimetry Spectroscopy Coordination 

Abbreviations

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

Notes

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.

Supplementary material

775_2006_154_MOESM1_ESM.doc (370 kb)
Supplementary material

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Copyright information

© SBIC 2006

Authors and Affiliations

  • Luc Guilloreau
    • 1
  • Luminita Damian
    • 2
    • 3
  • Yannick Coppel
    • 1
  • Honoré Mazarguil
    • 2
  • Mathias Winterhalter
    • 2
    • 3
  • Peter Faller
    • 1
  1. 1.Laboratoire de Chimie de CoordinationCNRS UPR 8241 (associated with University Toulouse III)Toulouse Cedex 4France
  2. 2.Institut de Pharmacologie et Biologie StructuraleToulouse Cedex 4France
  3. 3.International University BremenBremenGermany

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