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

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