Dependency of γ-secretase complex activity on the structural integrity of the bilayer

Research highlights: → Partial solubilization of membranes with CHAPSO can increase γ-secretase activity. → Completely solubilized γ-secretase is inactive. → Purified γ-secretase regains activity after reconstitution into lipid bilayers. → A broad range of detergents can be used to successfully reconstitute γ-secretase. -- Abstract: γ-secretase is a membrane protein complex associated with the production of Aβ peptides that are pathogenic in Alzheimer's disease. We have characterized the activity of γ-secretase complexes under a variety of detergent solubilization and reconstitution conditions, and the structural state of proteoliposomes by electron microscopy. We found that γ-secretase activity is highly dependent on the physical state or integrity of the membrane bilayer - partial solubilization may increase activity while complete solubilization will abolish it. The activity of well-solubilized γ-secretase can be restored to near native levels when properly reconstituted into a lipid bilayer environment.