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

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

SUBMITTER: Wong E

PROVIDER: S-EPMC6442608 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wong Eitan E Liao George P GP Chang Jerry C JC Xu Peng P Li Yue-Ming YM Greengard Paul P

Proceedings of the National Academy of Sciences of the United States of America 20190308 13

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 orienta ...[more]

PMID: 30850537

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