InterPro domain: IPR009294

This family consists of several eukaryotic Aph-1 proteins. Aph-1 is an essential subunit of the gamma-secretase complex, an endoprotease complex that catalyses the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signalling paradigm and as a key step in the pathogenesis of Alzheimer's disease [ 1 ]. It is thought that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. Aph-1 and Pen-2, two membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Co-expression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity [ 2 ].

1. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev. Cell 3, 85-97
2. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. U.S.A. 100, 6382-7