Substrate Docking to γ-Secretase Allows Access of γ-Secretase Modulators to an Allosteric Site

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Substrate Docking to γ-Secretase Allows Access of γ-Secretase Modulators to an Allosteric Site

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Title: Substrate Docking to γ-Secretase Allows Access of γ-Secretase Modulators to an Allosteric Site
Author: Uemura, Kengo; Farner, Katherine C.; Nasser-Ghodsi, Navine; Koo, Edward H.; Hashimoto, Tadafumi; Wolfe, Michael S.; Hyman, Bradley Theodore; Berezovska, Oksana

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Citation: Uemura, Kengo, Katherine C. Farner, Tadafumi Hashimoto, Navine Nasser-Ghodsi, Michael S. Wolfe, Edward H. Koo, Bradley T. Hyman, and Oksana Berezovska. 2010. Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site. Nature Communications 1:130.
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Abstract: 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.
Published Version: doi:10.1038/ncomms1129
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060602/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:5360620

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