A cascading activity-based probe sequentially targets E1–E2–E3 ubiquitin enzymes

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2016
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Mulder, Monique P.C.
Witting, Katharina
Berlin, Ilana
Pruneda, Jonathan N.
Wu, Kuen-Phon
Chang, Jer-Gung
El Oualid, Farid
Ovaa, Huib
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Nature Chemical Biology. 2016, 12(7), pp. 523-530. ISSN 1552-4450. eISSN 1552-4469. Available under: doi: 10.1038/nchembio.2084
Zusammenfassung

Post-translational modifications of proteins with ubiquitin (Ub) and ubiquitin-like modifiers (Ubls), orchestrated by a cascade of specialized E1, E2 and E3 enzymes, control a wide range of cellular processes. To monitor catalysis along these complex reaction pathways, we developed a cascading activity-based probe, UbDha. Similarly to the native Ub, upon ATP-dependent activation by the E1, UbDha can travel downstream to the E2 (and subsequently E3) enzymes through sequential trans-thioesterifications. Unlike the native Ub, at each step along the cascade, UbDha has the option to react irreversibly with active site cysteine residues of target enzymes, thus enabling their detection. We show that our cascading probe 'hops' and 'traps' catalytically active Ub-modifying enzymes (but not their substrates) by a mechanism diversifiable to Ubls. Our founder methodology, amenable to structural studies, proteome-wide profiling and monitoring of enzymatic activity in living cells, presents novel and versatile tools to interrogate Ub and Ubl cascades.

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570 Biowissenschaften, Biologie
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Chemical tools, Enzyme mechanisms, Post-translational modifications, Protein–protein interaction networks
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ISO 690MULDER, Monique P.C., Katharina WITTING, Ilana BERLIN, Jonathan N. PRUNEDA, Kuen-Phon WU, Jer-Gung CHANG, Johanna BIALAS, Marcus GRÖTTRUP, Farid EL OUALID, Huib OVAA, 2016. A cascading activity-based probe sequentially targets E1–E2–E3 ubiquitin enzymes. In: Nature Chemical Biology. 2016, 12(7), pp. 523-530. ISSN 1552-4450. eISSN 1552-4469. Available under: doi: 10.1038/nchembio.2084
BibTex
@article{Mulder2016-05-16casca-34794,
  year={2016},
  doi={10.1038/nchembio.2084},
  title={A cascading activity-based probe sequentially targets E1–E2–E3 ubiquitin enzymes},
  number={7},
  volume={12},
  issn={1552-4450},
  journal={Nature Chemical Biology},
  pages={523--530},
  author={Mulder, Monique P.C. and Witting, Katharina and Berlin, Ilana and Pruneda, Jonathan N. and Wu, Kuen-Phon and Chang, Jer-Gung and Bialas, Johanna and Gröttrup, Marcus and El Oualid, Farid and Ovaa, Huib}
}
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