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

doi:10.1083/jcb.200304014

Published 27 May 2003. doi:10.1083/jcb.200304014

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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

Report

Different cofactor activities in ${gamma}$ -secretase assembly

: evidence for a nicastrin–Aph-1 subcomplex

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 ${gamma}$ -secretase complex is required for intramembrane cleavageof 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 stepwisecoexpression approach to investigate the role of each new componentin ${gamma}$ -secretase assembly and activation. Coexpression of all fourproteins leads to high level accumulation of mature Psn andincreased proteolysis of Notch. Aph-1 and Nct may form a subcomplexthat stabilizes the Psn holoprotein at an early step in ${gamma}$ -secretaseassembly. Subcomplex levels of Aph-1 are down-regulated by stepwiseaddition of Psn, suggesting that Aph-1 might not enter the maturecomplex. In contrast, Pen-2 accumulates proportionally withPsn, and is associated with Psn endoproteolysis during ${gamma}$ -secretaseassembly. These results demonstrate that Aph-1 and Pen-2 areessential cofactors for Psn, but that they play different rolesin ${gamma}$ -secretase assembly and activation.

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

^* Abbreviations used in this paper: ${Delta}$ ECN, deletion of extracellularNotch; APP, amyloid precursor protein; dsRNA, double-strandedRNA; Nct, nicastrin; N(intra), intracellular Notch; Psn, presenilin;RNAi, RNA-mediated interference; S2, Schneider-2; SOP, sensoryorgan precursor.

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