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Biochem J. 2016 Feb 1;473(3):321-34. doi: 10.1042/BJ20150448.

The lipidome associated with the γ-secretase complex is required for its integrity and activity.

Author information

1
Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
2
Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH1015 Lausanne, Switzerland.
3
Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, CH-4058 Basel, Switzerland.
4
Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany patrick.fraering@epfl.ch shevchenko@mpi-cbg.de.
5
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.

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.

KEYWORDS:

intramembrane-cleaving protease; lipid microenvironment; lipid species; mass spectrometry; proteoliposomes; quantitative shotgun lipidomics; γ-secretase

PMID:
26811537
DOI:
10.1042/BJ20150448
[Indexed for MEDLINE]

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