Uemura, KengoFarner, Katherine C.Hashimoto, TadafumiNasser-Ghodsi, NavineWolfe, MichaelKoo, Edward H.Hyman, BradleyBerezovska, Oksana2011-12-062010Uemura, 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 1:130.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:5360620γ-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.en-UScell biologymolecular biologybiological sciencesneuroscienceJournal Article2011-12-0610.1038/ncomms1129