Summary
β- and γ-secretases, the proteases responsible for liberating the amyloid-β peptide (Aβ) from its precursor protein (APP), are considered important targets for the development of therapeutics for Alzheimer’s disease (AD). γ-Secretase has not been definitively identified, but its activity is closely linked to the multitransmembrane presenilins. Evidence using transition-state analogue inhibitors, site-directed mutagenesis, and molecular modeling suggests that γ-secretase is an aspartyl protease that catalyzes an intramembranous proteolysis. Two conserved transmembrane aspartates in presenilins are each critical for γ-secretase activity, and transition-state analogue γ-secretase inhibitors bind directly to presenilins. These results strongly suggest that presenilins are novel polytopic aspartyl proteases. The presenilins are also involved in the intramembranous proteolysis of the Notch receptor, a critical signaling event during cell fate decision in embryonic development. Transition-state analogue γ-secretase inhibitors also block the intramembranous cleavage of Notch, and the transmembrane aspartates of presenilins are required for this proteolysis as well. Thus, presenilins appear to play a similar role in the intramembranous processing of APP and Notch, raising concerns that toxic effects might result from chronic inhibition Notch signaling. We recently established in vitro γ-secretase assays using APP- and Notch-based substrates, and these assays should allow a rigorous biochemical comparison of these two related proteolytic processes. We also found that γ-secretase inhibitors can induce phenotypes mimicking Notch deficiencies in Drosophila, demonstrating that targeting this protease can interfere with Notch signaling in whole organisms.
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Wolfe, M.S., Esler, W.P., Kimberly, W.T., Selkoe, D.J. (2002). Presenilins, APP, and Notch: Proteolysis from Womb to Tomb. In: Christen, Y., Israël, A., De Strooper, B., Checler, F. (eds) Notch from Neurodevelopment to Neurodegeneration: Keeping the Fate. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55996-9_6
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