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


Authors: Wong, E.; Liao, G. P.; Chang, J. C.; Xu, P.; Li, Y. M.; Greengard, P.
Article Title: GSAP modulates γ-secretase specificity by inducing conformational change in PS1
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. © 2019 National Academy of Sciences. All Rights Reserved.
Keywords: conformational change; alzheimer’s disease; active-site labeling; gsap; γ-secretase modulation
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 116
Issue: 13
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2019-03-26
Start Page: 6385
End Page: 6390
Language: English
DOI: 10.1073/pnas.1820160116
PUBMED: 30850537
PROVIDER: scopus
PMCID: PMC6442608
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Yueming Li
    104 Li
  2. George Liao
    1 Liao