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

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 confo...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-03, Vol.116 (13), p.6385-6390
Main Authors: Wong, Eitan, Liao, George P., Chang, Jerry C., Xu, Peng, Li, Yue-Ming, Greengard, Paul
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Amyloid Precursor Protein Secretases - metabolism
Biological Sciences
Catalytic Domain
CRISPR-Cas Systems
Crosslinking
Gene Knockdown Techniques
HEK293 Cells
Humans
Kinetics
Notch1 protein
Peptide Fragments - metabolism
Presenilin 1
Presenilin-1 - chemistry
Proteins
Proteins - genetics
Proteins - metabolism
Receptor, Notch1
Secretase
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1820160116