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Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168

Author

Listed:
  • Tomio S. Takahashi

    (The University of Tokyo
    The University of Tokyo)

  • Yoshihiro Hirade

    (Osaka University)

  • Aya Toma

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Yusuke Sato

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Atsushi Yamagata

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Sakurako Goto-Ito

    (The University of Tokyo
    The University of Tokyo)

  • Akiko Tomita

    (Osaka University)

  • Shinichiro Nakada

    (Osaka University
    Osaka University)

  • Shuya Fukai

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

Abstract

The E3 ubiquitin (Ub) ligase RNF168 plays a critical role in the initiation of the DNA damage response to double-strand breaks (DSBs). The recruitment of RNF168 by ubiquitylated targets involves two distinct regions, Ub-dependent DSB recruitment module (UDM) 1 and UDM2. Here we report the crystal structures of the complex between UDM1 and Lys63-linked diUb (K63-Ub2) and that between the C-terminally truncated UDM2 (UDM2ΔC) and K63-Ub2. In both structures, UDM1 and UDM2ΔC fold as a single α-helix. Their simultaneous bindings to the distal and proximal Ub moieties provide specificity for Lys63-linked Ub chains. Structural and biochemical analyses of UDM1 elucidate an Ub-binding mechanism between UDM1 and polyubiquitylated targets. Mutations of Ub-interacting residues in UDM2 prevent the accumulation of RNF168 to DSB sites in U2OS cells, whereas those in UDM1 have little effect, suggesting that the interaction of UDM2 with ubiquitylated and polyubiquitylated targets mainly contributes to the RNF168 recruitment.

Suggested Citation

  • Tomio S. Takahashi & Yoshihiro Hirade & Aya Toma & Yusuke Sato & Atsushi Yamagata & Sakurako Goto-Ito & Akiko Tomita & Shinichiro Nakada & Shuya Fukai, 2018. "Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02345-y
    DOI: 10.1038/s41467-017-02345-y
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