Characterization of the ZnII binding to the peptide amyloid-beta1-16 linked to Alzheimer's disease.
Aggregation of the human peptide amyloid-beta (Abeta) is a key event in Alzheimer's disease (AD). Zinc ions play an important role in AD and in Abeta aggregation. In vitro, Zn(II) binds to Abeta and accelerates its aggregation. In this work we have investigated Zn(II) binding to the synthetic peptide Abeta1-16, which contains the metal-binding domain of Abeta. Cd(II) was used to probe the Zn(II) site. Abeta1-16 bound one equivalent of Zn(II) with an apparent dissociation constant (Kd) of 10(-4) M. This Kd value is in the same range as the Zn concentration needed to precipitate Abeta. Circular dichroism and NMR indicated predominantly random-coil secondary structures of apo-Abeta1-16, Zn(II)-Abeta1-16 and Cd(II)-Abeta1-16, which were all highly dynamic and flexible. The three histidines at positions 6, 13 and 14 were suggested to be ligands to Zn(II) and Cd(II). Evidence that the aspartate at position 1 served as a fourth ligand to Zn(II) and Cd(II) was found at pH 8.7. 111Cd(II) NMR showed a resonance at 84 ppm, in line with a mixed oxygen-/nitrogen-ligand environment. The tyrosine at position 10 could be excluded as a ligand.
Mekmouche
Yasmina
Y
Laboratoire de Chimie de Coordination, CNRS UPR 8241, Associated with the University of Toulouse III, France.
Coppel
Yannick
Y
Hochgräfe
Katja
K
Guilloreau
Luc
L
Talmard
Christine
C
Mazarguil
Honoré
H
Faller
Peter
P
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002104:Cadmium / Q000378:metabolism; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C433241:amyloid beta-protein (1-16); D002104:Cadmium; D014443:Tyrosine; D015032:Zinc