Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:24941111). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:24941111). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN. Predominantly located in the endoplasmic reticulum and in the cis-Golgi. Belongs to the PEN-2 family. 3D-structure analysis of the human homolog indicates that the membrane topology differs from the predictions. Contrary to predictions, the N-terminus contains two short helices that dip into the membrane, but do not cross it. The C-terminus contains the single transmembrane helix. This gives rise to a topology where the N-terminus is cytoplasmic and the C-terminus is lumenal.