Copper binding to the Alzheimer's disease amyloid precursor protein.
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.
Kong
Geoffrey K-W
GK
Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.
Miles
Luke A
LA
Crespi
Gabriela A N
GA
Morton
Craig J
CJ
Ng
Hooi Ling
HL
Barnham
Kevin J
KJ
McKinstry
William J
WJ
Cappai
Roberto
R
Parker
Michael W
MW
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D013057:Spectrum Analysis
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003300:Copper