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lüll 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 MWEur Biophys J 2008[Mar]; 37 (3): 269-79Alzheimer'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.|Alzheimer Disease/*physiopathology[MESH]|Amyloid beta-Peptides/metabolism[MESH]|Amyloid beta-Protein Precursor/*chemistry/*metabolism[MESH]|Animals[MESH]|Binding Sites[MESH]|Copper/*chemistry/metabolism[MESH]|Dimerization[MESH]|Down-Regulation[MESH]|Humans[MESH]|Models, Biological[MESH]|Molecular Sequence Data[MESH]|Protein Binding[MESH]|Protein Conformation[MESH]|Protein Processing, Post-Translational[MESH]|Spectrum Analysis[MESH] |