Building gamma-secretase: the bits and pieces.
gamma-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 gamma-secretase plays in development and neurogenesis. The most renowned substrates are the amyloid precursor protein and Notch, from which gamma-secretase liberates amyloid beta peptides and induces downstream signalling, respectively. gamma-Secretase is a multiprotein complex containing presenilin (which harbours the catalytic site), nicastrin, APH1 and PEN2. Its assembly occurs under tight control of ER-Golgi recycling regulators, which allows defined quantities of complexes to reach post-Golgi compartments, where gamma-secretase activity is regulated by multiple other 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 huge efforts, we are now only beginning to unravel the assembly, stoichiometry, activation and subcellular location of gamma-secretase.
Spasic
Dragana
D
Laboratory for Membrane Trafficking, Center for Human Genetics (KULeuven) and Department of Molecular and Developmental Genetics (VIB), O&N1, Gasthuisberg, Herestraat 49, Leuven, Belgium.
Annaert
Wim
W
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases