Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2000-06

AUTHORS

Yue-Ming Li, Min Xu, Ming-Tain Lai, Qian Huang, José L. Castro, Jillian DiMuzio-Mower, Timothy Harrison, Colin Lellis, Alan Nadin, Joseph G. Neduvelil, R. Bruce Register, Mohinder K. Sardana, Mark S. Shearman, Adrian L. Smith, Xiao-Ping Shi, Kuo-Chang Yin, Jules A. Shafer, Stephen J. Gardell

ABSTRACT

Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen. More... »

PAGES

689

Journal

TITLE

Nature

ISSUE

6787

VOLUME

405

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/35015085

    DOI

    http://dx.doi.org/10.1038/35015085

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1050813076

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/10864326


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