2008年7月
Phosphoinositides suppress gamma-secretase in both the detergent-soluble and -insoluble states
JOURNAL OF BIOLOGICAL CHEMISTRY
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- 巻
- 283
- 号
- 28
- 開始ページ
- 19283
- 終了ページ
- 19292
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1074/jbc.M705954200
- 出版者・発行元
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
gamma-Secretase is an aspartic protease that hydrolyzes type I membrane proteins within the hydrophobic environment of the lipid bilayer. Using the CHAPSO-solubilized gamma-secretase assay system, we previously found that gamma-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 gamma-secretase. Recently, level of secreted beta-amyloid protein was reported to be attenuated by increasing levels of phosphatidylinositol 4,5-diphosphate (PI(4,5)P(2)) in cultured cells. However, it is not clear whether PI(4,5)P(2) has a direct effect on gamma-secretase activity. In this study, we found that phosphoinositides directly inhibited CHAPSO-solubilized gamma-secretase activity. Interestingly, neither phosphatidylinositol nor inositol triphosphate altered gamma-secretase activity. PI(4,5)P(2) was also found to inhibit gamma-secretase activity in CHAPSO-insoluble membrane microdomains (rafts). Kinetic analysis of beta-amyloid protein production in the presence of PI(4,5)P(2) suggested a competitive inhibition. Even though phosphoinositides are minor phospholipids of the membrane, the concentration of PI(4,5)P(2) within the intact membrane has been reported to be in the range of 4-8 mM. The presence of PI(4,5)P(2)-rich rafts in the membrane has been reported in a range of cell types. Furthermore, gamma-secretase is enriched in rafts. Taking these data together, we propose that phosphoinositides potentially regulate gamma-secretase activity by suppressing its association with the substrate.
- リンク情報
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- DOI
- https://doi.org/10.1074/jbc.M705954200
- CiNii Articles
- http://ci.nii.ac.jp/naid/80019640279
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/18480063
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000257387600014&DestApp=WOS_CPL
- ID情報
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- DOI : 10.1074/jbc.M705954200
- ISSN : 0021-9258
- CiNii Articles ID : 80019640279
- PubMed ID : 18480063
- Web of Science ID : WOS:000257387600014