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

Abstract

Significance γ-Secretase cleaves multiple transmembrane proteins, but little is known about how it controls its substrate specificity. γ-Secretase activating protein (GSAP) has been reported to differentially activate γ-secretase for APP and Notch cleavages. The mechanism by which GSAP regulates γ-secretase specificity is elusive. Here, we demonstrate that GSAP directly regulates γ-secretase activity and specificity. Furthermore, GSAP functions as a switch between two forms of γ-secretase that have different activities for APP and Notch substrates, leading to different specificities. These findings open a new avenue for drug development through targeting the specificity of modifying proteins. This work also suggests that the association of GSAP with aging, Alzheimer’s disease, and Down syndrome could be attributed to the function of GSAP in the regulation of γ-secretase.