Figure 2.

The role of presenilins in the γ-secretase cleavage of Notch and βAPP. Notch is cleaved by tumor necrosis factor α converting enzyme (TACE), and its ligand binds to the part of Notch that remains attached to the membrane. βAPP is cleaved by either the γ-secretase pathway or the γ-secretase pathway to give a membrane-bound carboxy-terminal fragment (APP-CTF). Subsequent γ-secretase cleavage (in the transmembrane domain) of Notch or APP-CTF produces carboxy-terminal intracellular domains, NICD and AICD, respectively, which enter the nucleus and are thought to regulate gene expression. The γ-secretase cleavage of βAPP also produces the neurotoxic Aβ peptide, but only if βAPP has been first cleaved by γ-secretase (not γ-secretase). The γ-secretase complex includes, in addition to PS1, the presenilin-binding protein nicastrin; members of the Armadillo protein family, such as β-catenin, have also been detected in presenilin complexes, although their role is not understood. Aph-1 and Pen-2 may also participate in the γ-secretase complex.