title: The lipidome associated with the γ-secretase complex is required for its integrity and activity.
abstract: γ-Secretase is a multi-subunit membrane protease complex that catalyses the final intramembrane cleavage of the β-amyloid precursor protein (APP) during the neuronal production of amyloid-β peptides (Aβ), which are implicated as the causative agents of Alzheimer's disease (AD). In the present study, we report the reconstitution of a highly purified, active γ-secretase complex into proteoliposomes without exogenous lipids and provide the first direct evidence for the existence of a microenvironment of 53 molecular species from 11 major lipid classes specifically associated with the γ-secretase complex, including phosphatidylcholine and cholesterol. Importantly, we demonstrate that the pharmacological modulation of certain phospholipids abolishes both the integrity and the enzymatic activity of the intramembrane protease. Together, our findings highlight the importance of a specific lipid microenvironment for the structure and function of γ-secretase.
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ayciriex
authors.affiliation: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne, Switzerland.
authors.forename: Hermeto
authors.initials: H
authors.lastname: Gerber
authors.affiliation: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne, Switzerland.
authors.forename: Guillermo M Garcia
authors.initials: GM
authors.lastname: Osuna
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chami
authors.affiliation: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany patrick.fraering@epfl.ch shevchenko@mpi-cbg.de.
authors.forename: Andrej
authors.initials: A
authors.lastname: Shevchenko
authors.affiliation: Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne, Switzerland patrick.fraering@epfl.ch shevchenko@mpi-cbg.de.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D011510:Proteolipids / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D016564:Amyloid beta-Protein Precursor; D011510:Proteolipids; C020485:proteoliposomes; D053829:Amyloid Precursor Protein Secretases
keywords: intramembrane-cleaving protease; lipid microenvironment; lipid species; mass spectrometry; proteoliposomes; quantitative shotgun lipidomics; γ-secretase