期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：11
页码：6382-6387
DOI：10.1073/pnas.1037392100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{gamma} -Secretase catalyzes the intramembrane proteolysis of Notch, {beta}-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 heterodimers 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 {gamma}-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 {gamma}-secretase activity. These findings suggest that the four membrane proteins comprise the limiting components of {gamma}-secretase and coassemble to form the active enzyme in mammalian cells.
