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

Maximilian Fottner, Maria Weyh, Stefan Gaussmann, Dominic Schwarz, Michael Sattler and Kathrin Lang ()
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Maximilian Fottner: Lab for Synthetic Biochemistry, Technical University of Munich, Institute for Advanced Study, TUM-IAS
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
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
Kathrin Lang: Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26812-9

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