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Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain

Nature Structural & Molecular Biology volume 16, pages 1328–1330 (2009)Cite this article

Abstract

The protein kinase TAK1 is activated by binding to Lys63 (K63)-linked ubiquitin chains through its subunit TAB2. Here we analyze crystal structures of the TAB2 NZF domain bound to Lys63-linked di- and triubiquitin, revealing that TAB2 binds adjacent ubiquitin moieties via two distinct binding sites. The conformational constraints imposed by TAB2 on a Lys63 dimer cannot be adopted by linear chains, explaining why TAK1 cannot be activated by linear ubiquitination events.

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Figure 1: Structure of TAB2 NZF in complex with Lys63-linked di- and triubiquitin.
Figure 2: Validation and identification of additional two-sided NZF domains.
Figure 3: Specificity of TAB2.

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Acknowledgements

We would like to thank P. Cohen (Medical Research Council Protein Phosphorylation Unit), H. Scheel (Miltenyi Biotec), D. Veprintsev, A. Pobbati, R. Williams, O. Perisic, F. Gorrec, Y. Ye (Medical Research Council Laboratory of Molecular Biology) for help and reagents. Y.K., M.A. and A.B. are Medical Research Council Career Development Fellows.

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Author notes

  1. Masato Akutsu and Anja Bremm: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Yogesh Kulathu, Masato Akutsu, Anja Bremm & David Komander

  2. Miltenyi Biotec, Bergisch-Gladbach, Germany

    Kay Hofmann

Authors
  1. Yogesh Kulathu
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  2. Masato Akutsu
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  3. Anja Bremm
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  4. Kay Hofmann
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  5. David Komander
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Contributions

Y.K. designed and performed all experiments and analyzed the data, M.A. and A.B. contributed to experiments, K.H. provided NZF classification, and D.K. designed experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to David Komander.

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Supplementary Methods, Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 1673 kb)

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Kulathu, Y., Akutsu, M., Bremm, A. et al. Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain. Nat Struct Mol Biol 16, 1328–1330 (2009). https://doi.org/10.1038/nsmb.1731

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