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