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© The Rockefeller University Press, 0021-9525/2003/5/685 $5.00
The Journal of Cell Biology, Volume 161, Number 4, 685-690

Different cofactor activities in -secretase assembly

Yue Hu¹ and Mark E. Fortini²

¹ University of Pennsylvania School of Medicine, Philadelphia, PA 19104
² National Cancer Institute, Frederick, MD 21702

Address correspondence to M.E. Fortini, National Cancer Institute, Bldg. 560, Rm. 22-12, Frederick, MD 21702. Tel.: (301) 846-7599. Fax: (301) 846-1666. E-mail: fortini{at}ncifcrf.gov

The -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 -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 -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 -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 -secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in -secretase assembly and activation.

Key Words: presenilin; Pen-2; Notch; Drosophila; amyloid

^* Abbreviations used in this paper: ECN, deletion of extracellular Notch; APP, amyloid precursor protein; dsRNA, double-stranded RNA; Nct, nicastrin; N(intra), intracellular Notch; Psn, presenilin; RNAi, RNA-mediated interference; S2, Schneider-2; SOP, sensory organ precursor.

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