The amyloid-β protein (Aβ) is strongly implicated in the pathogenesis of Alzheimer's disease. The final step in the production of Aβ from the amyloid precursor protein (APP) is proteolysis by the unidentified γ-secretases. This cleavage event is unusual in that it apparently occurs within the transmembrane region of the substrate. Studies with substrate- based inhibitors together with molecular modeling and mutagenesis of the γ-secretase cleavage site of APP suggest that γ- secretases are aspartyl proteases that catalyze a novel intramembranous proteolysis. This proteolysis requires the presenilins, proteins with eight transmembrane domains that are mutated in most cases of autosomal dominant familial Alzheimer's disease. Two conserved transmembrane aspartates in presenilins are essential for γ-secretase activity, suggesting that presenilins themselves are γ-secretases. Moreover, presenilins also mediate the apparently intramembranous cleavage of the Notch receptor, an event critical for Notch signaling and embryonic development. Thus, if presenilins are γ-secretases, then they are also likely the proteases that cleave Notch within its transmembrane domain. Another protease, S2P, involved in the processing of the sterol regulatory element binding protein, is also a multipass integral membrane protein which cleaves within or very close to the transmembrane region of its substrate. Thus, presenilins and S2P appear to be members of a new type of polytopic protease with an intramembranous active site.
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