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

Kengo Uemura, Katherine C. Farner, Tadafumi Hashimoto, Navine Nasser-Ghodsi, Michael S. Wolfe, Edward H. Koo, Bradley T. Hyman and Oksana Berezovska ()
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Kengo Uemura: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital
Katherine C. Farner: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital
Tadafumi Hashimoto: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital
Navine Nasser-Ghodsi: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital
Michael S. Wolfe: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
Edward H. Koo: University of California San Diego
Bradley T. Hyman: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital
Oksana Berezovska: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital

Nature Communications, 2010, vol. 1, issue 1, 1-6

Abstract: Abstract γ-Secretase generates the peptides of Alzheimer's disease, Aβ40 and Aβ42, 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 Aβ42/Aβ40 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.

Date: 2010
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DOI: 10.1038/ncomms1129

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