Abstract
The β-amyloid precursor protein (APP), which is a key player in Alzheimer's disease, was recently reported to possess an Fe(II) binding site within its E2 domain which exhibits ferroxidase activity [Duce et al. 2010, Cell 142: 857]. The putative ligands of this site were compared to those in the ferroxidase site of ferritin. The activity was indirectly measured using transferrin, which scavenges the Fe(III) product of the reaction. A 22-residue synthetic peptide, named FD1, with the putative ferroxidase site of APP, and the E2 domain of APP were each reported to exhibit 40% of the ferroxidase activity of APP and of ceruloplasmin. It was also claimed that the ferroxidase activity of APP is inhibited by Zn(II) just as in ferritin. We measured the ferroxidase activity indirectly (i) by the incorporation of the Fe(III) product of the ferroxidase reaction into transferrin and directly (ii) by monitoring consumption of the substrate molecular oxygen. The results with the FD1 peptide were compared to the established ferroxidase activities of human H-chain ferritin and of ceruloplasmin. For FD1 we observed no activity above the background of non-enzymatic Fe(II) oxidation by molecular oxygen. Zn(II) binds to transferrin and diminishes its Fe(III) incorporation capacity and rate but it does not specifically bind to a putative ferroxidase site of FD1. Based on these results, and on comparison of the putative ligands of the ferroxidase site of APP with those of ferritin, we conclude that the previously reported results for ferroxidase activity of FD1 and – by implication – of APP should be re-evaluated.
Highlights
Human b-amyloid precursor protein (APP) is generally thought to play a key role in Alzheimer’s disease as the source of plaqueforming b-amyloid peptides (Ab) [1,2]
Kinetics with apparent positive cooperativity was observed and the Hill equation was used to fit the data with a Hill constant of 1.9 and a Vmax of 21 mM/min
In human H-chain ferritin the ferroxidase reaction occurs in the ferroxidase center made up of five residues [40] that can bind two Fe(II) simultaneously through eight coordination bonds to afford their oxidation by molecular oxygen (Fig. 1)
Summary
Human b-amyloid precursor protein (APP) is generally thought to play a key role in Alzheimer’s disease as the source of plaqueforming b-amyloid peptides (Ab) [1,2]. APP is a transmembrane protein made up of a large, multidomain extracellular extension, a small, single-pass transmembrane part, and a small intracellular extension (Figure 1A). Sequential processing of APP by the proteolytic enzymes b-secretase and csecretase liberates Ab: a sequence of typically 40 or 42 residues originally located partially in the membrane and for the remainder extracellularly. It is not known whether Ab in Alzheimer’s disease is a causative agent or a resulting product. The physiological role(s) of APP in healthy cells has not been firmly established
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