Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 29, Pages 10544-10549Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402171111
Keywords
Alzheimer's disease; intramembrane proteolysis; allosteric modulator; chemical biology; amyloid-beta protein
Categories
Funding
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan
- Ministry of Health, Labor, and Welfare, Japan (Comprehensive Research on Aging and Health)
- MEXT, Japan
- Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency
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gamma-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-beta (A beta) peptides. Recently, a series of compounds called.-secretase modulators (GSMs) has been shown to decrease the levels of long toxic A beta species (i.e., A beta 42), with a concomitant elevation of the production of shorter A beta species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of.-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of.-secretase to modulate A beta production.
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