Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator

gamma-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-beta (A beta) peptides. Recently, a series of compounds called.-secretase modulators (GSMs) has been shown to decrease the levels of long toxic A beta species (i.e., A beta 42), with a concomitant elevation of the production of shorter A beta species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of.-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of.-secretase to modulate A beta production.