Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1

The beta-amyloid precursor protein (beta-APP), which is involved in the pathogenesis of Alzheimer's disease, and the Notch receptor, which is responsible for critical signalling events during development, both undergo unusual proteolysis within their transmembrane domains by unknown gamma-secre...

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Bibliographic Details
Published in:Nature cell biology Vol. 2; no. 7; pp. 428 - 434
Main Authors: Esler, W P, Kimberly, W T, Ostaszewski, B L, Diehl, T S, Moore, C L, Tsai, J Y, Rahmati, T, Xia, W, Selkoe, D J, Wolfe, M S
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01-07-2000
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Summary:The beta-amyloid precursor protein (beta-APP), which is involved in the pathogenesis of Alzheimer's disease, and the Notch receptor, which is responsible for critical signalling events during development, both undergo unusual proteolysis within their transmembrane domains by unknown gamma-secretases. Here we show that an affinity reagent designed to interact with the active site of gamma-secretase binds directly and specifically to heterodimeric forms of presenilins, polytopic proteins that are mutated in hereditary Alzheimer's and are known mediators of gamma-secretase cleavage of both beta-APP and Notch. These results provide evidence that heterodimeric presenilins contain the active site of gamma-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheimer's disease.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/35017062