Abstract
Interaction of Cu ions with the amyloid-β (Aβ) peptide is linked to the development of Alzheimer’s disease; hence, determining the coordination of CuI and CuII ions to Aβ and the pathway of the CuI(Aβ)/CuII(Aβ) redox conversion is of great interest. In the present report, we use the room temperature X-ray absorption near edge structure to show that the binding sites of the CuI and CuII complexes are similar to those previously determined from frozen-solution studies. More precisely, the CuI is coordinated by the imidazole groups of two histidine residues in a linear fashion. However, an NMR study unravels the involvement of all three histidine residues in the CuI binding due to dynamical exchange between several set of ligands. The presence of an equilibrium is also responsible for the complex redox process observed by cyclic voltammetry and evidenced by a concentration-dependent electrochemical response.
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Notes
UV–vis and EPR quantification of reduced species indicate that with 1.5 equiv of dithionite per CuII ion (present work) the reduction is complete, whereas as previously observed (see [4]), with 1.2 equiv of ascorbate, 5–15% of the remaining CuII is detected.
We checked that the CuII(Aβ) sample does not photoreduce significantly; see Fig. S1.
Note that only on the basis of the XANES data the second model cannot be ruled out since a small portion of three-coordinate CuI species would not be detectable by XANES spectroscopy. Indeed, the XANES signature for related three-coordinate CuI species only differs from that of two-coordinate CuI by the intensity of the 1s → 4p transition, which is 0.6–0.7 in the former case [18]. However, such a three-coordinate CuI species may be disfavored because it is not in line with the sluggish reactivity toward O2 reported by Shearer and Szalai [4].
The relative intensities of the anodic and cathodic peaks are justified in the electronic supplementary material.
E½ is defined as ½(Ep,a + Ep,c) and ΔEp = |Ep,a − Ep,c|, where Ep,a (Ep,c) is defined as the potential of the maximum of the current intensity when scanning toward anodic (cathodic) potentials.
Note that we also checked that the buffer and chloride ions do not strongly affect the CV (see Fig. S8, and compare the dashed and solid lines in Fig. 4, voltammogram e, respectively).
CuII(Aβ) refers to the predominant complex present in solution at pH 6.7, whereas CuII(AβH) and CuII(AβH−1) refer to species that are also present but in lesser proportions.
Abbreviations
- Aβ:
-
Amyloid-β
- CV:
-
Cyclic voltammogram
- EXAFS:
-
Extended X-ray absorption fine structure
- PIPES:
-
Piperazine-1,4-bis(2-ethanesulfonic acid)
- ROS:
-
Reactive oxygen species
- SCE:
-
Saturated calomel electrode
- XAS:
-
X-ray absorption spectroscopy
- XANES:
-
X-ray absorption near edge structure
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Acknowledgments
This work was supported by a grant from the Agence Nationale de la Recherche, Programme Blanc (NT09-488591, “NEUROMETALS”). The staff of the SAMBA beamline at SOLEIL (SOLEIL Project 20080324) is gratefully acknowledged for help in performing the XAS experiments. We acknowledge Emmanuelle Mothes for technical assistance and Pierre Dorlet for fruitful discussions.
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Hureau, C., Balland, V., Coppel, Y. et al. Importance of dynamical processes in the coordination chemistry and redox conversion of copper amyloid-β complexes. J Biol Inorg Chem 14, 995–1000 (2009). https://doi.org/10.1007/s00775-009-0570-0
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DOI: https://doi.org/10.1007/s00775-009-0570-0