Phosphoinositides Suppress -Secretase in Both the Detergent-soluble and -insoluble States

Department of Neuropathology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2008; 283(28):19283-92. DOI: 10.1074/jbc.M705954200
Source: PubMed


γ-Secretase is an aspartic protease that hydrolyzes type I membrane proteins within the hydrophobic environment of the lipid
bilayer. Using the CHAPSO-solubilized γ-secretase assay system, we previously found that γ-secretase activity was sensitive
to the concentrations of detergent and phosphatidylcholine. This strongly suggests that the composition of the lipid bilayer
has a significant impact on the activity of γ-secretase. Recently, level of secreted β-amyloid protein was reported to be
attenuated by increasing levels of phosphatidylinositol 4,5-diphosphate (PI(4,5)P2) in cultured cells. However, it is not clear whether PI(4,5)P2 has a direct effect on γ-secretase activity. In this study, we found that phosphoinositides directly inhibited CHAPSO-solubilized
γ-secretase activity. Interestingly, neither phosphatidylinositol nor inositol triphosphate altered γ-secretase activity.
PI(4,5)P2 was also found to inhibit γ-secretase activity in CHAPSO-insoluble membrane microdomains (rafts). Kinetic analysis of β-amyloid
protein production in the presence of PI(4,5)P2 suggested a competitive inhibition. Even though phosphoinositides are minor phospholipids of the membrane, the concentration
of PI(4,5)P2 within the intact membrane has been reported to be in the range of 4–8 mm. The presence of PI(4,5)P2-rich rafts in the membrane has been reported in a range of cell types. Furthermore, γ-secretase is enriched in rafts. Taking
these data together, we propose that phosphoinositides potentially regulate γ-secretase activity by suppressing its association
with the substrate.

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