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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 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
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Fig4: 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

Mentions: We have produced three-dimensional atomic models of selected CuBDs from various organisms using homology modelling based on the sequence alignments shown in Fig. 3. The sequence alignment shows that the copper binding residues of human APP are not conserved in the APLP-1 family, C. elegans homologue APL-1 or D. melanogaster homologue APPL (Fig. 3). The replacement of the copper binding residues in human APLP-1 (Fig. 4b), C. elegans APL-1 (Fig. 4c) and D. melanogaster APPL (Fig. 4d) likely abolishes copper binding since residues are eliminated that are likely to be involved in copper coordination and the distance between the putative Cu(II) ion binding site to the surrounding residues increases (Fig. 4).Fig. 4


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 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
© Copyright Policy
Related In: Results  -  Collection

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

Fig4: 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
Mentions: We have produced three-dimensional atomic models of selected CuBDs from various organisms using homology modelling based on the sequence alignments shown in Fig. 3. The sequence alignment shows that the copper binding residues of human APP are not conserved in the APLP-1 family, C. elegans homologue APL-1 or D. melanogaster homologue APPL (Fig. 3). The replacement of the copper binding residues in human APLP-1 (Fig. 4b), C. elegans APL-1 (Fig. 4c) and D. melanogaster APPL (Fig. 4d) likely abolishes copper binding since residues are eliminated that are likely to be involved in copper coordination and the distance between the putative Cu(II) ion binding site to the surrounding residues increases (Fig. 4).Fig. 4

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