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Review
. 2008 Mar;37(3):269-79.
doi: 10.1007/s00249-007-0234-3. Epub 2007 Nov 21.

Copper binding to the Alzheimer's disease amyloid precursor protein

Geoffrey K-W Kong  1 , Luke A Miles, Gabriela A N Crespi, Craig J Morton, Hooi Ling Ng, Kevin J Barnham, William J McKinstry, Roberto Cappai, Michael W Parker
Affiliations
Review

Copper binding to the Alzheimer's disease amyloid precursor protein

Geoffrey K-W Kong et al. Eur Biophys J. 2008 Mar.

Abstract

Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce A beta levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.

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Figures

Fig. 1
Fig. 1
Domain arrangement of APP highlighting some important regions of the molecule. Cartoon ribbon pictures of known 3D structures of domains are shown at the top of the picture. The N-terminal growth factor domain (GFD; PDB id: 1MWP) is followed by CuBD (PDB ids: 1OWT, 2FKL, 2FJZ and 2FK3), an acidic-rich region, Kunitz-type protease inhibitor (KPI; PDB id: 1AAP) and OX2 domains that occur in some APP isoforms, a couple of glycosylated domains (D6a, sometimes called the E2 domain or CAPPD; PDB ids: 1TKN, 1RW6; followed by an unstructured domain we refer to as D6b), a transmembrane region (TM) and a cytoplasmic tail. The location of the Aβ region, a major component of Alzheimer’s disease plaques, is shown. The sequence of CuBD is shown with the copper binding ligands and Met170 in large bold type and the cysteines that are involved in disulfide bridges shown in underlinedbold type
Fig. 2
Fig. 2
Three-dimensional structure of CuBD (Kong et al. 2007a). a Ribbon picture of apo CuBD (PDB ids: 2FKL, 2FJZ and 2FK3) highlighting some of the side-chains that contribute to the copper binding site. b The Cu(II) coordination geometry in CuBD (PDB id: 2FK1) and comparison of the copper binding residues in the Cu(II)-bound and apo structures. The Cu(II)-bound structure is displayed in standard atomic colouring and the apo structure is in grey. The Cu(II) ion is indicated by the arrow, while ‘eq’ and ‘ax’ denote the equatorial and axial water molecules, respectively. C The Cu(I) coordination geometry in CuBD (PDB id: 2FK2) and a comparison of the copper binding site in the Cu(II)-bound and Cu(I)-bound CuBD structures. The Cu(II)- and Cu(I)-bound structures are shown in standard atomic colouring and in grey, respectively
Fig. 3
Fig. 3
A sequence alignment of CuBD from selected members of the APP superfamily. The prefixes h, r, m, d and c denote human, rat, mouse, Drosophila melanogaster and Caenorhabditis elegans, respectively. The N-terminal and C-terminal numbering of each CuBD are listed. Conserved residues are indicated by asterisks and coloured in aqua, colons indicate positions with very similar amino acid residues while dots indicate positions with some similarity. The copper binding residues of human APP CuBD and their equivalents in other homologues are coloured in orange
Fig. 4
Fig. 4
A comparison of the human APP CuBD copper binding site to the equivalent site in orthologues and paralogues. a Human APLP-2, b human APLP-1, c D. melanogaster APPL and d C. elegans APL-1. The human APP residues are shown in greensticks whereas the homology models are in ball-and-stick with the standard atomic colouring
Fig. 5
Fig. 5
Model of the APP growth factor domain docked onto CuBD. Note that an extra β-strand (coloured yellow), suggested by the modelling, has been inserted between the two domains to form an extended sheet
Fig. 6
Fig. 6
A ribbon diagram of CuBD124–189. Chains A and B are coloured in grey and green, respectively. Strand β0 of chain B is highlighted in red. The side-chains of the copper binding residues and Met170 are shown as blue sticks
Fig. 7
Fig. 7
A model of the putative effects of Cu(II) binding on APP dimerisation and Aβ production
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