Spasic Dragana, Annaert Wim
Laboratory for Membrane Trafficking, Center for Human Genetics (KULeuven) and Department of Molecular and Developmental Genetics (VIB), O&N1, Gasthuisberg, Herestraat 49, Leuven, Belgium.
J Cell Sci. 2008 Feb 15;121(Pt 4):413-20. doi: 10.1242/jcs.015255.
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.
γ-分泌酶是一种具有多种作用的天冬氨酸蛋白酶，负责在各种I型跨膜蛋白的大的胞外结构域脱落之后进行最终的膜内切割。其底物具有广泛的功能多样性，涉及细胞命运决定、黏附、神经突生长和突触形成，这突出了γ-分泌酶在发育和神经发生中所起的重要作用。最著名的底物是淀粉样前体蛋白和Notch，γ-分泌酶分别从它们中释放出淀粉样β肽并诱导下游信号传导。γ-分泌酶是一种多蛋白复合物，包含早老素（含有催化位点）、尼卡斯特林、APH1和PEN2。它的组装在ER-高尔基体循环调节因子的严格控制下发生，这使得一定数量的复合物能够到达高尔基体后区室，在那里γ-分泌酶的活性受到多种其他因素的调节。三维电子显微镜成像显示该复合物具有半透明的内部空间，这表明存在膜内蛋白水解所需的充满水的腔。尽管付出了巨大努力，但我们目前才刚刚开始了解γ-分泌酶的组装、化学计量、激活和亚细胞定位。
