Dynamics and cleavability of the alpha-cleavage site of APP(684-726) in different lipid environments

Marenchino, Marco, Williamson, Phillip T.F., Murri, Samuel, Zandomeneghi, Giorgia, Wunderli-Allenspach, Heidi, Meier, Beat H. and Kramer, Stefanie D. (2008) Dynamics and cleavability of the alpha-cleavage site of APP(684-726) in different lipid environments. Biophysical Journal, 95 (3), 1460-1473. (doi:10.1529/biophysj.108.129726). (PMID:18390599)

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 2H-Ala713, 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 Tc. The residue 15N-Ala692, which is in the vicinity of the ?-cleavage site, i.e., Lys687, showed less motion after reconstitution in distearoyl-phosphatidylcholine liposomes <Tc than in PhC, DMPC, or sphingomyelin vesicles. In all tested liposomal systems the ?-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 ?-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

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Contributors

Author: Phillip T.F. Williamson

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