Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 13, Pages 6385-6390Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1820160116
Keywords
Alzheimer's disease; gamma-secretase modulation; GSAP; active-site labeling; conformational change
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Funding
- NIH [R01NS096275, RF1AG057593, R01AG047781]
- Fisher Center for Alzheimer's Research
- JPB Foundation
- Institutional Training Grant [5T32GM073546]
- Memorial Sloan Kettering Cancer Center Support Grant/Core Grant [P30 CA008748]
- Commonwealth Foundation for Cancer Research
- Experimental Therapeutics Center of MSKCC
- William Randolph Hearst Fund in Experimental Therapeutics
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The mechanism by which gamma-secretase activating protein (GSAP) regulates gamma-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces gamma-secretase activity for A beta production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of gamma-secretase. Furthermore, using an active-site-directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of the PS1 N-terminal fragment and the PS1 C-terminal fragment, a region containing the active site of gamma-secretase. This work offers insight into how GSAP regulates gamma-secretase specificity.
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