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

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

Proceedings of the National Academy of Sciences of the United States of America (2019-03-10)
Eitan Wong, George P Liao, Jerry C Chang, Peng Xu, Yue-Ming Li, Paul Greengard
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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Anti-Amyloid β Antibody, clone W0-2, clone WO2, from mouse