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A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes

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  • Maximilian Fottner

    (Lab for Synthetic Biochemistry, Technical University of Munich, Institute for Advanced Study, TUM-IAS
    Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich)

  • Maria Weyh

    (Lab for Synthetic Biochemistry, Technical University of Munich, Institute for Advanced Study, TUM-IAS)

  • Stefan Gaussmann

    (Bavarian NMR Center, Department of Chemistry, Technical University of Munich
    Institute of Structural Biology, Helmholtz Zentrum München)

  • Dominic Schwarz

    (Lab for Synthetic Biochemistry, Technical University of Munich, Institute for Advanced Study, TUM-IAS)

  • Michael Sattler

    (Bavarian NMR Center, Department of Chemistry, Technical University of Munich
    Institute of Structural Biology, Helmholtz Zentrum München)

  • Kathrin Lang

    (Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich)

Abstract

The post-translational modification of proteins with ubiquitin (Ub) and Ub-like modifiers (Ubls) represents one of the most important regulators in eukaryotic biology. Polymeric Ub/Ubl chains of distinct topologies control the activity, stability, interaction and localization of almost all cellular proteins and elicit a variety of biological outputs. Our ability to characterize the roles of distinct Ub/Ubl topologies and to identify enzymes and receptors that create, recognize and remove these modifications is however hampered by the difficulty to prepare them. Here we introduce a modular toolbox (Ubl-tools) that allows the stepwise assembly of Ub/Ubl chains in a flexible and user-defined manner facilitated by orthogonal sortase enzymes. We demonstrate the universality and applicability of Ubl-tools by generating distinctly linked Ub/Ubl hybrid chains, and investigate their role in DNA damage repair. Importantly, Ubl-tools guarantees straightforward access to target proteins, site-specifically modified with distinct homo- and heterotypic (including branched) Ub chains, providing a powerful approach for studying the functional impact of these complex modifications on cellular processes.

Suggested Citation

  • Maximilian Fottner & Maria Weyh & Stefan Gaussmann & Dominic Schwarz & Michael Sattler & Kathrin Lang, 2021. "A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26812-9
    DOI: 10.1038/s41467-021-26812-9
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    1. Karen S. Harris & Thomas Durek & Quentin Kaas & Aaron G. Poth & Edward K. Gilding & Brendon F. Conlan & Ivana Saska & Norelle L. Daly & Nicole L. van der Weerden & David J. Craik & Marilyn A. Anderson, 2015. "Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    2. Yuanchen Dong & Shuwen Zhang & Zhaolong Wu & Xuemei Li & Wei Li Wang & Yanan Zhu & Svetla Stoilova-McPhie & Ying Lu & Daniel Finley & Youdong Mao, 2019. "Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome," Nature, Nature, vol. 565(7737), pages 49-55, January.
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