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

Abstract

The mechanism by which GSAP ({gamma}-secretase activating protein) 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 PS1-NTF and PS1-CTF, a region containing the active site of {gamma}-secretase. This work offers insight into how GSAP regulates {gamma}-secretase specificity.