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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Ayciriex Sophie, Gerber Hermeto, Osuna Guillermo M Garcia, Chami Mohamed, Stahlberg Henning, Shevchenko Andrej, Fraering Patrick C,
Project Electron Microscopy of Membrane Proteins
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Original article (peer-reviewed)

Journal The Biochemical journal
Volume (Issue) 473(3)
Page(s) 321 - 34
Title of proceedings The Biochemical journal
DOI 10.1042/bj20150448

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.
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