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Insights into ubiquitin chain architecture using Ub-clipping

Author

Listed:
  • Kirby N. Swatek

    (Medical Research Council Laboratory of Molecular Biology
    Max Planck Institute of Biochemistry)

  • Joanne L. Usher

    (Medical Research Council Laboratory of Molecular Biology)

  • Anja F. Kueck

    (Medical Research Council Laboratory of Molecular Biology)

  • Christina Gladkova

    (Medical Research Council Laboratory of Molecular Biology
    University of California San Francisco)

  • Tycho E. T. Mevissen

    (Medical Research Council Laboratory of Molecular Biology
    Harvard Medical School)

  • Jonathan N. Pruneda

    (Medical Research Council Laboratory of Molecular Biology
    Oregon Health and Science University)

  • Tim Skern

    (Medical University of Vienna)

  • David Komander

    (Medical Research Council Laboratory of Molecular Biology
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

Abstract

Protein ubiquitination is a multi-functional post-translational modification that affects all cellular processes. Its versatility arises from architecturally complex polyubiquitin chains, in which individual ubiquitin moieties may be ubiquitinated on one or multiple residues, and/or modified by phosphorylation and acetylation1–3. Advances in mass spectrometry have enabled the mapping of individual ubiquitin modifications that generate the ubiquitin code; however, the architecture of polyubiquitin signals has remained largely inaccessible. Here we introduce Ub-clipping as a methodology by which to understand polyubiquitin signals and architectures. Ub-clipping uses an engineered viral protease, Lbpro∗, to incompletely remove ubiquitin from substrates and leave the signature C-terminal GlyGly dipeptide attached to the modified residue; this simplifies the direct assessment of protein ubiquitination on substrates and within polyubiquitin. Monoubiquitin generated by Lbpro∗ retains GlyGly-modified residues, enabling the quantification of multiply GlyGly-modified branch-point ubiquitin. Notably, we find that a large amount (10–20%) of ubiquitin in polymers seems to exist as branched chains. Moreover, Ub-clipping enables the assessment of co-existing ubiquitin modifications. The analysis of depolarized mitochondria reveals that PINK1/parkin-mediated mitophagy predominantly exploits mono- and short-chain polyubiquitin, in which phosphorylated ubiquitin moieties are not further modified. Ub-clipping can therefore provide insight into the combinatorial complexity and architecture of the ubiquitin code.

Suggested Citation

  • Kirby N. Swatek & Joanne L. Usher & Anja F. Kueck & Christina Gladkova & Tycho E. T. Mevissen & Jonathan N. Pruneda & Tim Skern & David Komander, 2019. "Insights into ubiquitin chain architecture using Ub-clipping," Nature, Nature, vol. 572(7770), pages 533-537, August.
  • Handle: RePEc:nat:nature:v:572:y:2019:i:7770:d:10.1038_s41586-019-1482-y
    DOI: 10.1038/s41586-019-1482-y
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    Cited by:

    1. Fredrik Trulsson & Vyacheslav Akimov & Mihaela Robu & Nila Overbeek & David Aureliano Pérez Berrocal & Rashmi G. Shah & Jürgen Cox & Girish M. Shah & Blagoy Blagoev & Alfred C. O. Vertegaal, 2022. "Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Bianca D. M. Tol & Bjorn R. Doodewaerd & Guinevere S. M. Lageveen-Kammeijer & Bas C. Jansen & Cami M. P. Talavera Ormeño & Paul J. M. Hekking & Aysegul Sapmaz & Robbert Q. Kim & Angeliki Moutsiopoulou, 2023. "Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Yu-Hsuan Chen & Han-Hsiun Chen & Won-Jing Wang & Hsin-Yi Chen & Wei-Syun Huang & Chien-Han Kao & Sin-Rong Lee & Nai Yang Yeat & Ruei-Liang Yan & Shu-Jou Chan & Kuen-Phon Wu & Ruey-Hwa Chen, 2023. "TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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