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Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex

  1. Author:
    Hu, Y.
    Fortini, M. E.

  2. Author Address

    NCI, Bldg 560,Rm 22-12, Frederick, MD 21702 USA NCI, Frederick, MD 21702 USA Univ Penn, Sch Med, Philadelphia, PA 19104 USA Fortini ME NCI, Bldg 560,Rm 22-12, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Journal of Cell Biology
    1. 161
    2. 4
    3. Pages: 685-690
  4. Type of Article: Article
  1. Abstract:

    The 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.

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