Abstract
γ-Secretase is a membrane protein complex with an unusual aspartyl protease activity that catalyses the regulated intramembranous cleavage of the β-amyloid precursor protein (APP) to release the Alzheimer's disease (AD)-associated amyloid β-peptide (Aβ) and the APP intracellular domain (AICD)1. Here we show the reconstitution of γ-secretase activity in the yeast Saccharomyces cerevisiae, which lacks endogenous γ-secretase activity. Reconstituted γ-secretase activity depends on the presence of four complex components including presenilin (PS)1, nicastrin (Nct)2, APH-1 (refs 3–6) and PEN-2 (refs 4, 7), is associated with endoproteolysis of PS8, and produces Aβ and AICD in vitro. Thus, the biological activity of γ-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast.
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References
Haass, C. & Steiner, H. Trends Cell Biol. 12, 556–562 (2002).
Yu, G. et al. Nature 407, 48–54 (2000).
Goutte, C., Tsunozaki, M., Hale, V.A. & Priess, J.R. Proc. Natl Acad. Sci. USA 99, 775–779 (2002).
Francis, R. et al. Dev. Cell 3, 85–97 (2002).
Lee, S.F. et al. J. Biol. Chem. 277, 45013–45019 (2002).
Gu, Y. et al. J. Biol. Chem. 278, 7374–7380 (2002).
Steiner, H. et al. J. Biol. Chem. 277, 39062–39065 (2002).
Thinakaran, G. et al. Neuron 17, 181–190 (1996).
Esler, W.P. et al. Proc. Natl Acad. Sci. USA 99, 2720–2725. (2002).
Edbauer, D., Winkler, E., Haass, C. & Steiner, H. Proc. Natl Acad. Sci. USA 99, 8666–8671 (2002).
Steiner, H., Pesold, B. & Haass, C. FEBS Lett. 463, 245–249 (1999).
Wolfe, M.S. et al. Nature 398, 513–517 (1999).
Li, Y.M. et al. Nature 405, 689–694 (2000).
Yu, C. et al. J. Biol. Chem. 276, 43756–43760 (2001).
Sastre, M. et al. EMBO Rep. 2, 835–841 (2001).
Acknowledgements
We thank R. Nixon, A. Diehlmann and C. Miller for reagents, G. Basset for technical assistance and S. Eimer, H. Feldmann and B. Meier for helpful discussion. This work was supported by the Deutsche Forschungsgemeinschaft, the DIADEM project funded by the European Community, and the National Genome Research Network (NGFN).
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Edbauer, D., Winkler, E., Regula, J. et al. Reconstitution of γ-secretase activity. Nat Cell Biol 5, 486–488 (2003). https://doi.org/10.1038/ncb960
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DOI: https://doi.org/10.1038/ncb960
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