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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6385-6390. doi: 10.1073/pnas.1820160116. Epub 2019 Mar 8.

GSAP modulates γ-secretase specificity by inducing conformational change in PS1.

Author information

1
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
2
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
3
Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021.
4
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; liy2@mskcc.org greengard@rockefeller.edu.
5
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; liy2@mskcc.org greengard@rockefeller.edu.

Abstract

The mechanism by which γ-secretase activating protein (GSAP) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aβ production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-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 γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.

KEYWORDS:

Alzheimer’s disease; GSAP; active-site labeling; conformational change; γ-secretase modulation

PMID:
30850537
PMCID:
PMC6442608
DOI:
10.1073/pnas.1820160116
[Indexed for MEDLINE]
Free PMC Article

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