γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2

TLDR

γ‑Secretase is an intramembrane protease that cleaves Notch, β‑amyloid precursor protein, and other substrates, playing a key role in Alzheimer’s disease, yet its catalytic core—presenilin heterodimers with glycosylated nicastrin—remains poorly understood. We show that Aph‑1 and Pen‑2 directly bind presenilin and nicastrin, and that co‑expression of all four proteins increases presenilin heterodimer formation, nicastrin glycosylation, and γ‑secretase activity, indicating the four membrane proteins are the essential components that assemble into the active enzyme.

Abstract

γ-Secretase catalyzes the intramembrane proteolysis of Notch, β-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. This unusual protease has eluded identification, though evidence suggests that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. The formation of presenilin heterodimers from the holoprotein is tightly gated by unknown limiting cellular factors. Here we show that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to γ-secretase, associate directly with presenilin and nicastrin in the active protease complex. Coexpression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced γ-secretase activity. These findings suggest that the four membrane proteins comprise the limiting components of γ-secretase and coassemble to form the active enzyme in mammalian cells.