Kim Jinoh, Kleizen Bertrand, Choy Regina, Thinakaran Gopal, Sisodia Sangram S, Schekman Randy W
Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
J Cell Biol. 2007 Dec 3;179(5):951-63. doi: 10.1083/jcb.200709012.
Gamma-Secretase is responsible for proteolytic maturation of signaling and cell surface proteins, including amyloid precursor protein (APP). Abnormal processing of APP by gamma-secretase produces a fragment, Abeta(42), that may be responsible for Alzheimer's disease (AD). The biogenesis and trafficking of this important enzyme in relation to aberrant Abeta processing is not well defined. Using a cell-free reaction to monitor the exit of cargo proteins from the endoplasmic reticulum (ER), we have isolated a transient intermediate of gamma-secretase. Here, we provide direct evidence that the gamma-secretase complex is formed in an inactive complex at or before the assembly of an ER transport vesicle dependent on the COPII sorting subunit, Sec24A. Maturation of the holoenzyme is achieved in a subsequent compartment. Two familial AD (FAD)-linked PS1 variants are inefficiently packaged into transport vesicles generated from the ER. Our results suggest that aberrant trafficking of PS1 may contribute to disease pathology.
γ-分泌酶负责信号蛋白和细胞表面蛋白（包括淀粉样前体蛋白，即APP）的蛋白水解成熟过程。γ-分泌酶对APP的异常加工会产生一个片段，即Aβ(42)，它可能是导致阿尔茨海默病（AD）的原因。这种重要酶的生物合成及运输与异常的Aβ加工之间的关系尚未明确界定。我们利用无细胞反应来监测货物蛋白从内质网（ER）的输出，分离出了γ-分泌酶的一个瞬时中间体。在此，我们提供直接证据表明，γ-分泌酶复合物在依赖于COPII分选亚基Sec24A的内质网运输囊泡组装时或之前以无活性复合物的形式形成。全酶的成熟在后续区室中完成。两种与家族性AD（FAD）相关的PS1变体被低效地包装到从内质网产生的运输囊泡中。我们的结果表明，PS1的异常运输可能导致疾病病理。
Zotero 插件
