InterPro domain: IPR006639

Presenilin 1 (PSN1) and presenilin 2 (PSN2) are membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. They undergo tightly regulated endolytic processing to generate stable PSN C-terminal and N-terminal fragments that form the catalytic core of the gamma-secretase complex, an endoprotease complex that catalyses the intramembrane cleavage of integral membrane proteins such as Notch receptors [ 1 ].

Presenelins are related to the signal peptide peptidase (SPP) family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides. However, the SPPs work as single polypeptides. SPP catalyses intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognised by the immune system, and are required in the processing of the hepatitis C virus core protein [ 2 , 3 ].

This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family, clan AD).

1. Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases. Biol. Chem. 391, 839-47
2. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215-8
3. Structural analysis of hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase. J. Virol. 86, 7818-28