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

William P. Esler, W. Taylor Kimberly, Beth L. Ostaszewski, Thekla S. Diehl, Chad L. Moore, Jui Yi Tsai, Talat Rahmati, Weiming Xia, Dennis J. Selkoe, Michael S. Wolfe

Research output: Contribution to journalArticle

486 Scopus citations

Abstract

The β-amyloid precursor protein (β-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 γ-secretases. Here we show that an affinty reagent designed to interact with the active site of γ-secretase binds directly and specifically to he terodimeric forms of presenilins, polytopic proteins that are mutated in hereditary Alzheimer's and are known mediators of γ-secretase cleavage of both β-APP and Notch. These results provide evidence that heterodimeric presenilins contain the active site of 7-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheirner's disease.

Original languageEnglish (US)
Pages (from-to)428-434
Number of pages7
JournalNature Cell Biology
Volume2
Issue number7
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Cell Biology

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