Substrate docking to ?-secretase allows access of ?-secretase modulators to an allosteric site.

ABSTRACT: ?-Secretase generates the peptides of Alzheimer's disease, A?(40) and A?(42), by cleaving the amyloid precursor protein within its transmembrane domain. ?-Secretase also cleaves numerous other substrates, raising concerns about ?-secretase inhibitor off-target effects. Another important class of drugs, ?-secretase modulators, alter the cleavage site of ?-secretase on amyloid precursor protein, changing the A?(42)/A?(40) ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for ?-secretase modulators is uncertain, with some data suggesting that they function on ?-secretase, whereas others support their binding to the amyloid precursor. In this paper we address this controversy by using a fluorescence resonance energy transfer-based assay to examine whether ?-secretase modulators alter Presenilin-1/?-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the ?-secretase allosteric site is located within the ?-secretase complex, but substrate docking is needed for ?-secretase modulators to access this site.

SUBMITTER: Uemura K 

PROVIDER: S-EPMC3060602 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature