Structural and thermodynamical properties of CuII amyloid-beta16/28 complexes associated with Alzheimer's disease.
The aggregation of the peptide amyloid-beta (Abeta) to form amyloid plaques is a key event in Alzheimer's disease. It has been shown that CuII can bind to soluble Abeta 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 Abeta16 and Abeta28, models of the soluble Abeta. Moreover, different spectroscopic methods were applied. The studies revealed new insights into these CuII-Abeta 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 Abeta28 but not in Abeta16; (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.
Guilloreau
Luc
L
Laboratoire de Chimie de Coordination, CNRS UPR 8241 (associated with University Toulouse III), 205 route de Narbonne, 31077, Toulouse Cedex 4, France.
Damian
Luminita
L
Coppel
Yannick
Y
Mazarguil
Honoré
H
Winterhalter
Mathias
M
Faller
Peter
P
D000544:Alzheimer Disease / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001224:Aspartic Acid; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D013057:Spectrum Analysis; D013816:Thermodynamics; D014443:Tyrosine
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C433241:amyloid beta-protein (1-16); C084358:amyloid beta-protein (1-28); D001224:Aspartic Acid; D014443:Tyrosine; D003300:Copper