Biogenesis of gamma-secretase early in the secretory pathway.
Biogenesis of gamma-secretase early in the secretory pathway.
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DOI：
10.1083/jcb.200709012
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发表时间：
2007-12-03
期刊：
影响因子：
--
通讯作者：
Schekman RW
中科院分区：
文献类型：
--
作者：
Kim J;Kleizen B;Choy R;Thinakaran G;Sisodia SS;Schekman RW
γ-分泌酶负责信号和细胞表面蛋白（包括淀粉样前体蛋白（APP））的蛋白水解成熟。γ-分泌酶对APP的异常加工产生一个片段Aβ42，这可能是阿尔茨海默病（AD）的原因。与异常Aβ加工相关的这种重要酶的生物起源和运输尚未明确。利用无细胞反应监测货物蛋白从内质网（ER）的退出，我们已经分离出γ-分泌酶的瞬时中间体。在这里，我们提供了直接的证据表明，γ-分泌酶复合物是在依赖于COPII分选亚基Sec 24 A的ER转运囊泡组装时或组装之前形成的无活性复合物。全酶的成熟在随后的隔室中实现。两个家族性AD（FAD）-连锁PS1变体被低效地包装到由ER产生的运输囊泡中。我们的研究结果表明，PS1的异常贩运可能有助于疾病的病理。
γ-Secretase is responsible for proteolytic maturation of signaling and cell surface proteins, including amyloid precursor protein (APP). Abnormal processing of APP by γ-secretase produces a fragment, Aβ42, that may be responsible for Alzheimer's disease (AD). The biogenesis and trafficking of this important enzyme in relation to aberrant Aβ 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 γ-secretase. Here, we provide direct evidence that the γ-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.
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影响因子：
5.3
作者：
Berezovska, O;Lleo, A;Hyman, BT
通讯作者：
Hyman, BT
影响因子：
64.5
作者：
Mossessova, E;Bickford, LC;Goldberg, J
通讯作者：
Goldberg, J
影响因子：
4.8
作者：
LaVoie, MJ;Fraering, PC;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
4.8
作者：
Kim, J;Hamamoto, S;Schekman, R
通讯作者：
Schekman, R
DOI：
10.1073/pnas.022523499
发表时间：
2002-01-22
影响因子：
11.1
作者：
Goutte, C;Tsunozaki, M;Priess, JR
通讯作者：
Priess, JR