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Papers In Press, published online ahead of print April 15, 2004
Laboratoire de Pharmacologie Expérimentale, UCL 54.10, Brussels 1200
Corresponding Author: octave{at}nchm.ucl.ac.be
The cleavage of the transmembrane amyloid precursor protein (APP) by {beta}-secretase leaves the C-terminal fragment of APP, C99, anchored in the plasma membrane. C99 is subsequently processed by {gamma}-secretase, an unusual aspartyl protease activity largely dependent on presenilins (PS), generating the amyloid {beta}-peptide (Ab) that accumulates in the brain of patients with Alzheimer’s disease. If PS have been suggested to be the catalytic core of this proteolytic activity, a number of other proteins mandatory for {gamma}-secretase cleavage have also been discovered. The exact role of PS in the {gamma}-secretase activity remains a matter of debate, since cells devoid of PS still produce some forms of Ab. Here, we used insect cells expressing C99 to demonstrate that expression of presenilin 1 (PS1), which binds C99, not only increases the production of Ab by these cells but also increases the intracellular levels of C99 to the same extent. Using pulse-chase experiments, we established that this results from an increased half-life of C99 in cells expressing PS1. In CHO cells producing C99 from full-length human APP, similar results were observed. Finally, we show that a functional inhibitor of {gamma}-secretase does not alter the ability of PS1 to increase the intracellular levels of C99. This suggests that binding of PS1 to C99 does not necessarily lead to its immediate cleavage by {gamma}-secretase, which could be a spatio-temporally regulated or an induced event, and brings biochemical evidence for the existence of a substrate docking site on PS1.
J. Biol. Chem, 10.1074/jbc.M312710200
Submitted on November 20, 2003
Revised on April 14, 2004
Accepted on April 15, 2004
Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of {gamma}-secretase activity
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