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Citation
Stempfle, D., Kanwar, R., Loewer, A., Fortini, M.E., Merdes, G. (2010). In vivo reconstitution of gamma-secretase in Drosophila results in substrate specificity.  Mol. Cell. Biol. 30(13): 3165--3175.
FlyBase ID
FBrf0211009
Publication Type
Research paper
Abstract
The intramembrane aspartyl protease gamma-secretase plays a fundamental role in several signaling pathways involved in cellular differentiation and has been linked with a variety of human diseases, including Alzheimer's disease. Here, we describe a transgenic Drosophila model for in vivo-reconstituted gamma-secretase, based on expression of epitope-tagged versions of the four core gamma-secretase components, Presenilin, Nicastrin, Aph-1, and Pen-2. In agreement with previous cell culture and yeast studies, coexpression of these four components promotes the efficient assembly of mature, proteolytically active gamma-secretase. We demonstrate that in vivo-reconstituted gamma-secretase has biochemical properties and a subcellular distribution resembling those of endogenous gamma-secretase. However, analysis of the cleavage of alternative substrates in transgenic-fly assays revealed unexpected functional differences in the activity of reconstituted gamma-secretase toward different substrates, including markedly reduced cleavage of some APP family members compared to cleavage of the Notch receptor. These findings indicate that in vivo under physiological conditions, additional factors differentially modulate the activity of gamma-secretase toward its substrates. Thus, our approach for the first time demonstrates the overall functionality of reconstituted gamma-secretase in a multicellular organism and the requirement for substrate-specific factors for efficient in vivo cleavage of certain substrates.
PubMed ID
PubMed Central ID
PMC2897587 (PMC) (EuropePMC)
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Merdes, 2010.2.24, P{UAS-alphaAPLP2.LV} construct and insertion from Gunter Merdes. [FBrf0210424]
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Associated Information
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Mol. Cell. Biol.
    Title
    Molecular and Cellular Biology
    Publication Year
    1981-
    ISBN/ISSN
    0270-7306
    Data From Reference
    Alleles (34)
    Gene Groups (2)
    Genes (21)
    Physical Interactions (13)
    Natural transposons (1)
    Insertions (4)
    Experimental Tools (5)
    Transgenic Constructs (27)