Journal of Biological Chemistry
Volume 277, Issue 47, 22 November 2002, Pages 45013-45019
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MECHANISMS OF SIGNAL TRANSDUCTION
Mammalian APH-1 Interacts with Presenilin and Nicastrin and Is Required for Intramembrane Proteolysis of Amyloid-β Precursor Protein and Notch*

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Presenilin and nicastrin are essential components of the γ-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-β precursor protein (APP) and Notch. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian APH-1 (mAPH-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilinor nicastrin, the inactivation of endogenousmAPH-1 using small interfering RNAs results in the decrease of presenilin levels, accumulation of γ-secretase substrates (APP carboxyl-terminal fragments), and reduction of γ-secretase products (amyloid-β peptides and the intracellular domains of APP and Notch). These data indicate that mAPH-1 is probably a functional component of the γ-secretase complex required for the intramembrane proteolysis of APP and Notch.

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*

This work was supported by the UT Southwestern Endowed Scholars Program for Biomedical Research and the UT Southwestern Alzheimer Disease Center Pilot Grant 35279.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.