Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 2: Dependence of Cu(II) binding sites with Aβ sequences

Copper ions have been proposed to play a central role in the amyloid cascade process linked to the development of Alzheimer disease (AD). Involvement in both the amyloid-beta (A beta) aggregation process and reactive oxygen species (ROS) production has been considered. In the last 15 years, many studies regarding copper(II) coordination to A beta have been reported with divergent conclusions and a consensual binding scheme is not reached yet. They include (i) spectroscopic and thermodynamic investigations of copper(II) coordination to chemically modified peptides (mutants, truncated peptides, etc.) and subsequent analysis of the differences obtained with the native A beta peptide; (ii) spectroscopic characterization of copper(II) coordination to A beta via direct methods, such as advanced EPR techniques and FTIR spectroscopy combined with the use of C-13, N-15 specifically labeled peptides and NMR. More recently, copper(II) coordination to naturally occurring modified peptides of biological relevance such as murine A beta, H6R and A2V mutants, and truncated forms at position 3, have also been studied. In the present review, the objective is to give a report as exhaustive as possible of the literature structural data on copper(II) binding to the A beta peptides and to its modified forms and to sort out contradicting results. Such discrepancies are mainly due to the unstructured nature of the copper binding site in A beta. Concomitantly, copper(II) coordination has been revealed to be highly dynamic with equilibrium between amino-acid residues of identical nature for one binding position. As a direct consequence, the copper(II) coordination spheres proposed represent the most reasonable models obtained with data available at present. At physiological pH, two copper(II) binding sites, noted components land II, coexist. The transition between land II is pH-driven and the pH where the two components are found in a 1:1 ratio (PKa(I/II)) is approx. 7.8, with I (resp. II) predominant at lower (resp. higher) pH. In I and II, the equatorial binding sites of copper(II) are {-NH2 (Asp1), CO (Asp1-Ala2), N-im(tau), (His6), N-im(pi) (His13 or His14)} and {-NH2 (Asp1), N- (Asp1-Ala2), CO (Ala2-Glu3), N-im(tau) (His6) or N-im (His13 or His14)}, respectively. land II were clearly (and by consensus) identified by their EPR parameters, g(parallel to) = 2.27 +/- 0.01, A(parallel to) = 183 +/- 5 x 10(-4) cm(-1) and g(parallel to) = 2.23 +/- 0.01, A(parallel to) = 160 +/- 5 x 10(-4) cm(-1), respectively. Given examples of copper(II) binding to other naturally occurring A beta peptides include binding to the murine A beta peptide, differing from the human A beta by three point mutations, and to the H6R mutant. Copper(II) binding to murine and human A beta peptides diverges by the pK(a)(I/II) value (approx. 6.2 for the former instead of 7.8) and by the nature of the peptide functional group which undergoes deprotonation between I and II, i.e. the Gly5-His6 bond compared with the Asp1-Ala2 bond in the human case. Copper(II) binding to the H6R mutant is characterized by a pK(a)(I/II) value of approx. 7.3, a decrease induced by the unfavorable coordination of both His13 and His14 in component I. (C) 2012 Elsevier B.V. All rights reserved.