title: Kinetics of the Interactions between Copper and Amyloid-β with FAD Mutations and Phosphorylation at the N terminus.
abstract: Mutations and post-translational modifications of amyloid-β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.
authors.affiliation: Institute of Chemical Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Girvan
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-0034, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyake
authors.affiliation: Institute of Chemical Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Teng
authors.affiliation: Institute of Chemical Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.|Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Branch
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. l.ying@imperial.ac.uk.|Institute of Chemical Biology, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. l.ying@imperial.ac.uk.
authors.forename: Liming
authors.initials: L
authors.lastname: Ying
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009154:Mutation; D010766:Phosphorylation
chemical_list: D016229:Amyloid beta-Peptides; D003300:Copper
keywords: amyloid beta-peptides; copper; fluorescence spectroscopy; kinetics; reaction mechanism