Abstract
X-ray absorption spectroscopy data show different metal binding site structures in β-amyloid peptides according to whether they are complexed with Cu2+ or Zn2+ ions. While the geometry around copper is stably consistent with an intra-peptide binding with three metal-coordinated Histidine residues, the zinc coordination mode depends on specific solution conditions. In particular, different sample preparations are seen to lead to different geometries around the absorber that are compatible with either an intra- or an inter-peptide coordination mode. This result reinforces the hypothesis that assigns different physiological roles to the two metals, with zinc favoring peptide aggregation and, as a consequence, plaque formation.
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Notes
The total absorption coefficient, μ(k), is the quantity actually measured, from which the structural signal, χ(k) is defined as the relative oscillations, with respect to the absorption coefficient, μ 0(k), of the isolated absorber (Cu or Zn). In formulae
$$ \chi (k) = \frac{{\mu (k) - \mu _{0} (k)}} {{\mu _{0} (k)}}, $$(1)where k is the photo-electron wave vector which is related to the incident photon energy E and the ionization energy E 0 by the obvious relation
$$ {k = {\sqrt {\frac{{2m(E - E_{0} )}} {{{\hbar }^{2} }},} }} $$(2)with m the electron mass and ħ the Planck constant.
We recall that this is precisely the situation one encounters when Histidine residues are bound to the absorber. The non-negligible MS contributions due to presence of an imidazole ring can be usefully exploited to get a clear-cut determination of the number of Histidine residues directly bound to the metal (Meneghini and Morante 1998; Morante et al. 2004).
According to Binsted et al. (1992), the number of independent data points, Nind, is defined as
$$ N_{{{\text{ind}}}} = \frac{{2{\text{ $ \Delta $ }}k{\text{ $ \Delta $ }}r}} {\pi } + j, $$where Δk=k max−k min is the interval of momenta over which data have been taken, Δr is the width of the shell containing all the scatterers that are taken into account in the fit and j is a small positive integer not larger than 2 which to be conservative we take to be equal to 0.
A critical role in the oxidative stress and neuro-toxicity induced by Aβ-peptides has been attributed to Methionine (Butterfield and Boyd-Kimball 2005).
The R-factor of the fit is computed as follows:
$$ R = {\sum\limits_{i = 1}^P {\frac{1} {{w_{i} }}} }{\left| {\chi ^{{\exp }} (k_{i} ) - \chi ^{{{\text{fit}}}} (k_{i} )} \right|}, $$(3)where χexp and χfit are the experimental and theoretical data, respectively, and the sum is over the number, P, of the k values at which data were collected. The “weighting” parameter w i is defined by the formula
$$ w_{i} = \frac{1} {{k^{n}_{i} }}{\sum\limits_{j = 1}^P {k^{n}_{j} {\left| {\chi ^{{\exp }} (k_{j} )} \right|}} }, $$(4)where the integer n is selected in such a way that the amplitude of the EXAFS oscillations in k nχexp(k) do not die away at large values of k. In this paper, we took n=3 It is a consolidated experience that for complex biological molecules a fit can be considered adequately good for values of R in the interval between 20 and 40% (Binsted 1998).
For completeness and to fix our notations, we recall how the parameters introduced in the text enter the formula for the measured absorption coefficient. For simplicity, we report formulae valid in the single scattering approximation. In this case, the theoretical EXAFS signal has the expression
$$ \chi (k) = S^{2}_{0} {\sum\limits_l {\frac{{N_{l} }} {{kr^{2}_{l} }}} }{\left| {f_{l} (k,\pi )} \right|}\sin (2kr_{l} + \varphi _{l} (k))\,{\text{e}}^{{ - 2\sigma ^{2}_{l} k^{2} }} \,{\text{e}}^{{ - 2r_{l} /\lambda (k)}} , $$(5)where the sum runs over the different coordination shells around the absorber. N l is the number of scatterers of the l-th shell, located at a distance r l from the absorber and σ l 2 is the Debye–Waller factor. |f l(k,π)| is the modulus of the back-scattering amplitude and ϕ(k) the total scattering phase. Finally, \( S^{2}_{0} \) is an empirical quantity that accounts for all the many-body losses in photo-absorption processes and λ(k) is the photo-electron mean free path. For MS processes, a formally similar expression can be derived, in which r l represents the length of the full MS path. Modulus and phase functions are now more complicated expressions which depend on each scattering event along the MS path (Lee and Pendry 1975; Benfatto et al. 1986; Gurman et al. 1986; Koningsberger and Prins 1988; Rehr and Albers 1990).
Error on angles are somewhat large and are of the order of 20%.
Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
Amyloid β-peptide
- AβPP:
-
β-Amyloid precursor protein
- XAS:
-
X-ray absorption spectroscopy
- EMBL:
-
European Molecular Biology Laboratory
- DESY:
-
Deutsches Elektronen Synchrotron
- EXAFS:
-
Extended X-ray absorption fine structure
- MDB:
-
Metallo-protein Database and Browser
- MS:
-
Multiple scattering
- XANES:
-
X-ray absorption near edge
- DW:
-
Debye–Waller
- PDB:
-
Protein Data Bank
- FT:
-
Fourier transform
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Acknowledgements
We are very grateful to G.C. Rossi for discussions and a careful reading of the manuscript. We would also like to thank G. La Penna for useful suggestions and discussions. This work was partly supported by INFM, INFN, CNR, ITC and the “European Community-Research Infrastructure Action” under the FP6 “Structuring the European Research Area Programme” contract number RII3/CT/2004/5060008.
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The work presented in this paper started with the invaluable collaboration of G. Menestrina and we would like to dedicate it to his memory.
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Stellato, F., Menestrina, G., Serra, M.D. et al. Metal binding in amyloid β-peptides shows intra- and inter-peptide coordination modes. Eur Biophys J 35, 340–351 (2006). https://doi.org/10.1007/s00249-005-0041-7
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DOI: https://doi.org/10.1007/s00249-005-0041-7