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pubmed-article:12771124pubmed:abstractTextThe gamma-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative gamma-secretase components have been identified-presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in gamma-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in gamma-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during gamma-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in gamma-secretase assembly and activation.lld:pubmed
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pubmed-article:12771124pubmed:articleTitleDifferent cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex.lld:pubmed
pubmed-article:12771124pubmed:affiliationUniversity of Pennsylvania School of Medicine, Philadelphia 19104, USA.lld:pubmed
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pubmed-article:12771124pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
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