title: Ligand-field and ligand-binding analysis of the active site of copper-bound Aβ associated with Alzheimer's disease.
abstract: Alzheimer's disease (AD) patients show abnormally high concentrations of Cu(2+) in the amyloid β plaques. This invokes that Cu(2+) might play a crucial role in the onset of AD. The last few decades of research have also shown that Cu(2+) plays a significant role in the aggregation of Aβ plaques in the brain and the generation of oxidative stress. Because the crystal structures of Cu-Aβ are yet to be obtained, there are various proposed models for the Cu(2+) coordination environment of Aβ peptides. In this study, we have used the truncated hydrophilic part of the native Aβ peptide to probe the Cu(2+) coordination site of the peptide, using a combination of spectroscopy and exogenous ligand-binding studies. It is evident from our study that Aβ(1-16) binds 1 equiv of Cu(2+) and yet shows an equilibrium between two species with a pK(a) of ~8.1. Ligand-field analysis of absorption and circular dichroism spectroscopy data indicates five-coordinate geometry for both components. We investigate the effect of azide and 8-hydroxyquinoline binding to Cu-Aβ and demonstrate the presence of a water-derived ligand and a second exchangeable ligand coordinated to copper at physiological pH, along the equatorial plane of a square-pyramidal active site.
authors: Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India 700032.
authors: Chandradeep
authors: C
authors: Ghosh
authors: Somdatta Ghosh
authors: SG
authors: Dey
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D009942:Organometallic Compounds; D003300:Copper