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

Tomio S. Takahashi, Yoshihiro Hirade, Aya Toma, Yusuke Sato, Atsushi Yamagata, Sakurako Goto-Ito, Akiko Tomita, Shinichiro Nakada () and Shuya Fukai ()
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Tomio S. Takahashi: The University of Tokyo
Yoshihiro Hirade: Osaka University
Aya Toma: The University of Tokyo
Yusuke Sato: The University of Tokyo
Atsushi Yamagata: The University of Tokyo
Sakurako Goto-Ito: The University of Tokyo
Akiko Tomita: Osaka University
Shinichiro Nakada: Osaka University
Shuya Fukai: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02345-y

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