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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2
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γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2

机译：γ-秘密酶是一种膜蛋白复合物，由早老素，尼卡斯汀，aph-1和pen-2组成

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摘要

γ-Secretase catalyzes the intramembrane proteolysis of Notch, β-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. This unusual protease has eluded identification, though evidence suggests that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. The formation of presenilin het-erodimers from the holoprotein is tightly gated by unknown limiting cellular factors. Here we show that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to γ-secretase, associate directly with presenilin and nicastrin in the active protease complex. Coexpression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced γ-secretase activity. These findings suggest that the four membrane proteins comprise the limiting components of γ-secretase and coassemble to form the active enzyme in mammalian cells.
机译：γ-分泌酶催化Notch，β-淀粉样前体蛋白和其他底物的膜内蛋白水解，这是新信号范式的一部分，也是阿尔茨海默氏病发病机理中的关键步骤。尽管证据表明早老素异二聚体包含催化位点，并且尼卡斯汀的高度糖基化形式与其结合，但这种不寻常的蛋白酶尚未被鉴定。由全蛋白形成的早老素异二聚体被未知的限制性细胞因子严格控制。在这里，我们显示Aph-1和Pen-2，这两个最近鉴定出的与γ-分泌酶遗传相关的膜蛋白，与活性蛋白酶复合物中的早老素和尼卡斯特林直接相关。所有四种蛋白质的共表达导致早老素异二聚体显着增加，尼古斯汀的完全糖基化和增强的γ-分泌酶活性。这些发现表明，四种膜蛋白包含γ-分泌酶的限制性成分，并在哺乳动物细胞中共同装配形成活性酶。

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