Dec 2, 2010

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

Nature Communications
Kengo UemuraOksana Berezovska


γ-Secretase generates the peptides of Alzheimer's disease, Aβ(40) and Aβ(42), by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ(42)/Aβ(40) ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for γ-secretase modulators is uncertain, with some data suggesting that they function on γ-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 γ-secretase modulators alter Presenilin-1/γ-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the γ-secretase allosteric site is located within the γ-secretase complex, but substrate docking is needed for γ-secretase modulators to access this site.

Mentioned in this Paper

APP protein, human
Allosteric Site
Transmembrane Domain
Amyloid Beta Precursor Protein Measurement
Cytokinesis of the Fertilized Ovum
Alzheimer's Disease
Amyloid Neuropathies
Docking -molecular Interaction

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