Journal of Cell Science vol:121 issue:4 pages:413-420
γ-Secretase is a promiscuous aspartyl protease responsible for the final intramembrane cleavage of various type I transmembrane proteins after their large ectodomains are shed. The vast functional diversity of its substrates, which are involved in cell fate decisions, adhesion, neurite outgrowth and synapse formation, highlights the important role γ-secretase plays in development and neurogenesis. The most renowned substrates are the amyloid precursor protein and Notch, from which γ-secretase liberates amyloid γ peptides and induces downstream signaling, respectively. γ-Secretase is a multiprotein complex containing presenilin –which harbours the catalytic site-, nicastrin, APH-1 and PEN-2. Its assembly occurs under tight control of ER-Golgi recycling regulators allowing defined quantities of complexes to reach post-Golgi compartments where the activity is regulated by yet other multiple factors. 3D-EM rendering reveals a complex with a translucent inner space suggesting the presence of a water-filled cavity required for intramembrane proteolysis. Despite the huge efforts, we are now only beginning to unravel the assembly, stoichiometry, activation and subcellular location of γ-secretase.