PEN2

PEN2, also known as presenilin enhancer 2, is a small transmembrane protein that is one of the core components of the gamma-secretase complex. In humans, the PEN2 protein is encoded by the PSENEN gene. It is conserved across many eukaryotes and is expressed in a variety of tissues.

Within the gamma-secretase complex, PEN-2 plays a critical role in the maturation and activity of the protease. It is required for the endoproteolysis of presenilin, the catalytic subunit of gamma-secretase, and thereby contributes to the formation of the active gamma-secretase complex. The complex, composed of presenilin, nicastrin, APH-1, and PEN-2, functions to cleave type I transmembrane proteins within the membrane.

The best known substrates of gamma-secretase include the amyloid precursor protein (APP) and Notch receptors. Cleavage of APP by gamma-secretase releases amyloid-beta peptides, whereas Notch processing influences signaling pathways essential for cell differentiation and development. Because PEN-2 is essential for gamma-secretase activity, changes in PEN-2 expression or function can impact both APP processing and Notch signaling.

Clinical research has examined PEN-2 and gamma-secretase components in relation to aging and neurodegenerative disease, particularly Alzheimer’s disease, where alterations in APP processing and amyloid-beta production are central features. Direct pathogenic mutations in PEN-2 are uncommon, but understanding its role helps elucidate how gamma-secretase regulation affects disease-related pathways.