Evidence for a copper-binding superfamily of the amyloid precursor protein.
The amyloid precursor protein (APP) copper-binding domain (CuBD) has been shown to reduce Cu(II) to Cu(I) and to mediate copper-induced oxidation in vitro. However, little is known about copper binding to the homologous domains of APP and APP family paralogs and orthologs (including amyloid precursor-like proteins from Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans) and their effects on Cu-induced oxidation and Cu(I) formation. Here, we show that APP homologues with and without conserved histidine residues at positions 147, 149, and 151 all bind Cu(II). Oxidized peptides were the kinetically favored products of the redox reaction of CuBDs promoting the reduction of Cu(II) to Cu(I). These results reveal a molecular phylogeny-based divergence that has taken place between the ancestral Drosophila APPL and C. elegans APL-1 and the recently evolved APP lineage of CuBDs. Whereas higher species CuBDs have a decreased affinity for Cu(II) and high Cu(II) reducing activities, ancestral CuBDs form very tight binding sites for Cu(II) ions and have low Cu(II) reducing activities. Thus, the APP lineage displays a gain in activity toward promoting Cu(II) reduction and Cu(I) release. The findings suggests that the Cu(II)-binding equilibrium at the phylogenetic stage of Drosophila APPL and C. elegans APL-1 is shifted from the exchangeable Cu(II) pool to the tightly bound, nonexchangeable pool and that ancestral CuBDs may exert antioxidation activities in vivo. The more recently evolved homologues of human APP appear to take advantage of unique redox properties for yet unknown biological functions.
Simons
Andreas
A
ZMBH-Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany.
Ruppert
Thomas
T
Schmidt
Carsten
C
Schlicksupp
Andrea
A
Pipkorn
Rüdiger
R
Reed
Jennifer
J
Masters
Colin L
CL
White
Anthony R
AR
Cappai
Roberto
R
Beyreuther
Konrad
K
Bayer
Thomas A
TA
Multhaup
Gerd
G
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003300:Copper / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
D016564:Amyloid beta-Protein Precursor; D003300:Copper