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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2000-06-09

AUTHORS

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

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 affinity reagent designed to interact with the active site of γ-secretase binds directly and specifically to heterodimeric 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 γ-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheimer’s disease. More... »

PAGES

428-434

Journal

TITLE

Nature Cell Biology

ISSUE

7

VOLUME

2

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/35017062

    DOI

    http://dx.doi.org/10.1038/35017062

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1026279799

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/10878808


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    41 schema:description 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 affinity reagent designed to interact with the active site of γ-secretase binds directly and specifically to heterodimeric 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 γ-secretase, and validate presenilins as principal targets for the design of drugs to treat and prevent Alzheimer’s disease.
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