title: Dynamics and Cleavability at the alpha-cleavage site of APP(684-726) in different lipid environments.
abstract: The occurrence of late-onset Alzheimer's disease has been related to the lipid homeostasis. We tested whether the membrane lipid environment affects the dynamics and cleavability of a model peptide corresponding to the amino acid sequence 684-726 of the amyloid precursor protein APP reconstituted in liposomes. Solid-state NMR with (2)H-Ala(713), which is located within the putative transmembrane domain, suggested that the peptide observes less rotational motion in egg phosphatidylcholine (PhC) membranes than in dimyristoyl-phosphatidylcholine (DMPC) bilayers above the main phase transition temperature T(c). The residue (15)N-Ala(692), which is in the vicinity of the alpha-cleavage site, i.e., Lys(687), showed less motion after reconstitution in distearoyl-phosphatidylcholine liposomes <T(c) than in PhC, DMPC, or sphingomyelin vesicles. In all tested liposomal systems the alpha-cleavage site was accessible for hydrolysis by trypsin. However, the catalytic rate constant was higher in the PhC and DMPC than in the sphingomyelin and distearoyl-phosphatidylcholine systems. In conclusion, the dynamics of APP(684-726) on the transmembrane level as well as the motion of the alpha-cleavage site and its hydrolysis by a model enzyme are dependent on the bilayer characteristics. This could be relevant for the processing of APP in vivo.
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich (Swiss Federal Institute of Technology Zurich), Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Marenchino
authors.forename: Philip T F
authors.initials: PT
authors.lastname: Williamson
authors.forename: Samuel
authors.initials: S
authors.lastname: Murri
authors.forename: Giorgia
authors.initials: G
authors.lastname: Zandomeneghi
authors.forename: Heidi
authors.initials: H
authors.lastname: Wunderli-Allenspach
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D008081:Liposomes / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D016564:Amyloid beta-Protein Precursor; D008081:Liposomes; D008563:Membrane Lipids