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.
TY - JOUR
T1 - Ligand-field and ligand-binding analysis of the active site of copper-bound Aβ associated with Alzheimer's disease.
AU - Ghosh,Chandradeep,
AU - Dey,Somdatta Ghosh,
Y1 - 2013/01/18/
PY - 2013/1/22/entrez
PY - 2013/1/22/pubmed
PY - 2013/7/24/medline
SP - 1318
EP - 27
JF - Inorganic chemistry
JO - Inorg Chem
VL - 52
IS - 3
N2 - 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.
SN - 1520-510X
UR - https://www.unboundmedicine.com/medline/citation/23330670/Ligand_field_and_ligand_binding_analysis_of_the_active_site_of_copper_bound_Aβ_associated_with_Alzheimer's_disease_
L2 - https://doi.org/10.1021/ic301865n
DB - PRIME
DP - Unbound Medicine
ER -
