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

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 and Stephen J. Gardell ()
Additional contact information
Yue-Ming Li: Department of Biological Chemistry Merck Research Laboratories
Min Xu: Department of Biological Chemistry Merck Research Laboratories
Ming-Tain Lai: Department of Biological Chemistry Merck Research Laboratories
Qian Huang: Department of Biological Chemistry Merck Research Laboratories
José L. Castro: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
Jillian DiMuzio-Mower: Department of Biological Chemistry Merck Research Laboratories
Timothy Harrison: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
Colin Lellis: Department of Biological Chemistry Merck Research Laboratories
Alan Nadin: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
Joseph G. Neduvelil: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
R. Bruce Register: Department of Biological Chemistry Merck Research Laboratories
Mohinder K. Sardana: Department of Biological Chemistry Merck Research Laboratories
Mark S. Shearman: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
Adrian L. Smith: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories
Xiao-Ping Shi: Department of Biological Chemistry Merck Research Laboratories
Kuo-Chang Yin: Department of Biological Chemistry Merck Research Laboratories
Jules A. Shafer: Department of Biological Chemistry Merck Research Laboratories
Stephen J. Gardell: Department of Biological Chemistry Merck Research Laboratories

Nature, 2000, vol. 405, issue 6787, 689-694

Abstract: Abstract Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic peptides Aβ40 and Aβ42—the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients1. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of γ-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease2,3 increase the production of Aβ42 (refs 4,5,6), the more amyloidogenic peptide; γ-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos7; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of γ-secretase to catalyse processing of APP within its transmembrane domain8. 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 γ-secretase cofactor, or helps to colocalize γ-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent γ-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 γ-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.

Date: 2000
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DOI: 10.1038/35015085

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