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Issue 1, 2014
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Quantification of copper binding to amyloid precursor protein domain 2 and its Caenorhabditis elegans ortholog. Implications for biological function§

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Abstract

Aberrant regulation of transition metals and the resultant disregulation of neuronal reactive oxygen species (ROS) are considered significant in the etiology of Alzheimer's disease (AD). We determined the solution structure of the D2 domain of APL-1 (APL1-D2), the Caenorhabditis elegans ortholog of the amyloid precursor protein domain 2 (APP-D2). The copper binding affinities of APL1-D2 and APP-D2 were estimated and the ability of their copper complexes to promote formation of ROS was tested. The two protein domains are isostructural, consisting of a three-stranded β-sheet packed against a short α-helix in a βαββ fold. A six-residue insert in APL1-D2, absent in APP-D2, forms an extended loop. The putative copper binding ligands in APP-D2 are not conserved in APL1-D2 and this delineates a clear difference between them. APL1-D2 and APP-D2 bind one equivalent of Cu(I) weakly, with dissociation constants KD ∼10−8.6 M and ∼10−10 M, respectively, and up to two equivalents of Cu(II) with KD values in the range 10−6 –10−8 M. The relative abilities of APL1-D2, APP-D2 and amyloid-β (Aβ) copper complexes to generate H2O2 correspond to their copper binding affinities. Copper affinities for Aβ (KD ∼ 10−10 M for both Cu(I) and Cu(II)) and APP-D2 are in a range allowing redox cycling to occur, albeit less efficiently for APP-D2. However, APL1-D2 binds Cu(I) and Cu(II) too weakly to sustain catalysis which further suggests that it plays no significant role in copper handling in C. elegans. Overall, the data are consistent with a possible role in copper homeostasis for APP-D2, but not APL1-D2.

Graphical abstract: Quantification of copper binding to amyloid precursor protein domain 2 and its Caenorhabditis elegans ortholog. Implications for biological function

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Publication details

The article was received on 21 Sep 2013, accepted on 18 Nov 2013 and first published on 19 Nov 2013


Article type: Paper
DOI: 10.1039/C3MT00258F
Metallomics, 2014,6, 105-116

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    Quantification of copper binding to amyloid precursor protein domain 2 and its Caenorhabditis elegans ortholog. Implications for biological function

    S. L. Leong, T. R. Young, K. J. Barnham, A. G. Wedd, M. G. Hinds, Z. Xiao and R. Cappai, Metallomics, 2014, 6, 105
    DOI: 10.1039/C3MT00258F

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