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Copper binding to the Alzheimer's disease amyloid precursor protein.

Kong GK, Miles LA, Crespi GA, Morton CJ, Ng HL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW - Eur. Biophys. J. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.

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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Related in: MedlinePlus

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
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Fig3: 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

Mentions: One of the consequences of Cu(II) binding to APP is thought to be neuronal toxicity which has been demonstrated so far in cultured neurones. The hypothesised role of CuBD in neuronal toxicity is that the bound Cu(II) is reduced to Cu(I), which can then lead to lipoprotein peroxidation and free radicals that damage the cell (White et al. 2002). CuBD is one of the best conserved domains within the APP superfamily (Fig. 3). Surprisingly, the effect of copper binding varies between the orthologues and paralogues. For example, it has been shown that the presence of Cu(II) salts in primary murine neuronal cultures causes greater cell death in wild-type neurones compared to APP−/− neurones whereas there is no difference between wild-type and APLP2−/− neurones (White et al.1999a). Lipoprotein peroxidation is enhanced by Cu(II)-treated ectodomain of human APP and APLP2, whereas neither the non-metallated forms of those proteins nor Cu(II)-metallated human APLP1 show increased peroxidation above background (White et al. 2002). Cu(II)-bound CuBD of human APP appears sufficient in the generation of Cu(I) and causing neuronal cell death (White et al. 2002).Fig. 3


Copper binding to the Alzheimer's disease amyloid precursor protein.

Kong GK, Miles LA, Crespi GA, Morton CJ, Ng HL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW - Eur. Biophys. J. (2007)

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
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921068&req=5

Fig3: 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
Mentions: One of the consequences of Cu(II) binding to APP is thought to be neuronal toxicity which has been demonstrated so far in cultured neurones. The hypothesised role of CuBD in neuronal toxicity is that the bound Cu(II) is reduced to Cu(I), which can then lead to lipoprotein peroxidation and free radicals that damage the cell (White et al. 2002). CuBD is one of the best conserved domains within the APP superfamily (Fig. 3). Surprisingly, the effect of copper binding varies between the orthologues and paralogues. For example, it has been shown that the presence of Cu(II) salts in primary murine neuronal cultures causes greater cell death in wild-type neurones compared to APP−/− neurones whereas there is no difference between wild-type and APLP2−/− neurones (White et al.1999a). Lipoprotein peroxidation is enhanced by Cu(II)-treated ectodomain of human APP and APLP2, whereas neither the non-metallated forms of those proteins nor Cu(II)-metallated human APLP1 show increased peroxidation above background (White et al. 2002). Cu(II)-bound CuBD of human APP appears sufficient in the generation of Cu(I) and causing neuronal cell death (White et al. 2002).Fig. 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.

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.

Show MeSH
Related in: MedlinePlus