Presenilins, APP, and Notch: Proteolysis from Womb to Tomb

摘要

beta- and gamma-secretases, the proteases responsible for liberating the amyloid-P peptide (Abeta) from its precursor protein (APP), are considered important targets for the development of therapeutics for Alzheimer's disease (AD). gamma-Secretase has not been definitively identified, but its activity is closely linked to the multi-transmembrane presenilins. Evidence using transition-state analogue inhibitors, site-directed mutagenesis, and molecular modeling suggests that gamma-secretase is an aspartyl protease that catalyzes an intramembranous proteolysis. Two conserved transmembrane aspartates in presenilins are each critical for gamma-secretase activity, and transition-state analogue gamma-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 gamma-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 gamma-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 gamma-secretase inhibitors can induce phenotypes mimicking Notch deficiencies in Drosophila, demonstrating that targeting this protease can interfere with Notch signaling in whole organisms.