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Novel chemical proteomics methods to discover targets of cysteine reactive molecules

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Defense Thèse de doctorat : Univ. Genève, 2017 - Sc. 5125 - 2017/09/20
Abstract In this thesis, we develop a new mass spectrometry-based chemoproteomic method that allows detection and monitoring of up to 3000 reactive cysteines in any given cellular proteome via strategic use of two clickable probes with complementary selectivity profiles, iodoacetamide-alkyne and ethynyl benziodoxolone JW-RF-010. With this approach, we identify the targets of the natural product curcumin and found that it covalently modifies several key players of cellular signaling, including the kinase CSNK1G. Furthermore, we apply our profiling method to identify molecular targets of the natural product deoxyelephantopin and found that it covalently modifies the zinc-bound Cys190 in a zinc finger motif of PPARγ. Finally, we elucidate the molecular mechanism of thiol-mediated uptake. We show that appendage of a single asparagusic acid residue is sufficient to ensure cellular uptake of proapoptotic peptides. Experiments document covalent bond formation between asparagusic acid and two cysteines on the transferrin receptor resulting in subsequent endocytic uptake.
Keywords Chemical ProteomicsCysteineLC-MS/MSMass spectrometryNatural productsCurcuminDeoxyelephantopinAspAAsparagusic acidThiol-mediated uptakeCPDTFRC
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URN: urn:nbn:ch:unige-977247
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Research group Groupe Adibekian
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ABEGG, Daniel. Novel chemical proteomics methods to discover targets of cysteine reactive molecules. Université de Genève. Thèse, 2017. https://archive-ouverte.unige.ch/unige:97724

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Deposited on : 2017-10-18

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