title: Effect of the Synaptic Plasma Membrane on the Stability of the Amyloid Precursor Protein Homodimer.
abstract: The proteolytic cleavage of the transmembrane (TM) domain of the amyloid precursor protein (APP) releases amyloid-β (Aβ) peptides, which accumulation in the brain tissue is an early indicator of Alzheimer's disease. We used multiscale molecular dynamics simulations to investigate the stability of APP-TM dimer in realistic models of the synaptic plasma membrane (SPM). Between the two possible dimerization motifs proposed by NMR and EPR, namely G709XXXA713 and G700XXXG704XXXG708, our study revealed that the dimer promoted by the G709XXXA713 motif is not stable in the SPM due to the competition with highly unsaturated lipids that constitute the SPM. Under the same conditions, the dimer promoted by the G700XXXG704XXXG708 motif is instead the most stable species and likely the most biologically relevant. Independently of the dimerization state, both these motifs can be involved in the recruitment of cholesterol molecules.
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL) , Lausanne 1015, Switzerland.|Swiss Institute of Bioinformatics (SIB) , Lausanne 1015, Switzerland.
authors: Martina
authors: M
authors: Audagnotto
authors: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94143, United States.
authors: Thomas
authors: T
authors: Lemmin
authors: Inserm, U1054 Montpellier, France.|Université de Montpellier, CNRS, UMR 5048 , Centre de Biochimie Structurale, U1054 Montpellier, France.
authors: Alessandro
authors: A
authors: Barducci
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL) , Lausanne 1015, Switzerland.|Swiss Institute of Bioinformatics (SIB) , Lausanne 1015, Switzerland.
authors: Matteo
authors: M
authors: Dal Peraro
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry*; D008958:Models, Molecular
chemical_list: D053829:Amyloid Precursor Protein Secretases