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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 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
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Fig6: 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

Mentions: We have determined the crystal structure of a longer length fragment of CuBD124–189 to 2.5 Å resolution (Kong et al. 2007a). This crystal from was found to have two CuBD molecules in the asymmetric unit. An interesting feature of this structure is that the two molecules interact head-to-head via new β-strand (β0) involving residues 127–129 of one molecule hydrogen bonding onto strand β2 of a neighbouring molecule to form an extended β-sheet (Fig. 6). The interaction buries about 1,550 Å2 of surface area between the molecules. However, there are a few contacts between the two chains. The new strand β0 of chain B provides some of those interactions through hydrogen bonds from the backbone amides of Ala126 (B) and Leu127 (B) to the backbone carbonyl of Met170 (A), and that from the backbone carbonyl of Tyr168 (A) to backbone amide of Val129 (B). There are van der Waals contacts between the rings of His147 (A) and Phe135 (B), between the backbone of Gly175 (A) and side-chain of Leu171 (B), between the side-chains of Asp177 (A) and His137 (B), and a hydrogen bond between the backbone amide of Asp177 (A) and carboxylate group of Glu183 (B). Strand β0 is also within van der Waals distance of the copper binding site of the latter molecule. However, it is unlikely that the dimer seen in this crystal form has a significant existence in solution because there is no evidence of dimerisation of CuBD124–189 in the NMR experiment (Barnham et al. 2003). Nevertheless, the structure shows that N-terminal residues 124–132 of CuBD have an inherent propensity to form a β-strand and thus lends support to the suggestion discussed above that this region of CuBD could be induced to form a strand leading to the extended β-sheet with GFD in intact APP (Fig. 5).Fig. 6


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 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
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: 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
Mentions: We have determined the crystal structure of a longer length fragment of CuBD124–189 to 2.5 Å resolution (Kong et al. 2007a). This crystal from was found to have two CuBD molecules in the asymmetric unit. An interesting feature of this structure is that the two molecules interact head-to-head via new β-strand (β0) involving residues 127–129 of one molecule hydrogen bonding onto strand β2 of a neighbouring molecule to form an extended β-sheet (Fig. 6). The interaction buries about 1,550 Å2 of surface area between the molecules. However, there are a few contacts between the two chains. The new strand β0 of chain B provides some of those interactions through hydrogen bonds from the backbone amides of Ala126 (B) and Leu127 (B) to the backbone carbonyl of Met170 (A), and that from the backbone carbonyl of Tyr168 (A) to backbone amide of Val129 (B). There are van der Waals contacts between the rings of His147 (A) and Phe135 (B), between the backbone of Gly175 (A) and side-chain of Leu171 (B), between the side-chains of Asp177 (A) and His137 (B), and a hydrogen bond between the backbone amide of Asp177 (A) and carboxylate group of Glu183 (B). Strand β0 is also within van der Waals distance of the copper binding site of the latter molecule. However, it is unlikely that the dimer seen in this crystal form has a significant existence in solution because there is no evidence of dimerisation of CuBD124–189 in the NMR experiment (Barnham et al. 2003). Nevertheless, the structure shows that N-terminal residues 124–132 of CuBD have an inherent propensity to form a β-strand and thus lends support to the suggestion discussed above that this region of CuBD could be induced to form a strand leading to the extended β-sheet with GFD in intact APP (Fig. 5).Fig. 6

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