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Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin

Author

Listed:
  • Matthias Zebisch

    (Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Yang Xu

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
    Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, College of Life Science, Jilin University)

  • Christos Krastev

    (Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Bryan T. MacDonald

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • Maorong Chen

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • Robert J. C. Gilbert

    (Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Xi He

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • E. Yvonne Jones

    (Wellcome Trust Centre for Human Genetics, University of Oxford)

Abstract

The four R-spondin (Rspo) proteins are secreted agonists of Wnt signalling in vertebrates, functioning in embryogenesis and adult stem cell biology. Through ubiquitination and degradation of Wnt receptors, the transmembrane E3 ubiquitin ligase ZNRF3 and related RNF43 antagonize Wnt signalling. Rspo ligands have been reported to inhibit the ligase activity through direct interaction with ZNRF3 and RNF43. Here we report multiple crystal structures of the ZNRF3 ectodomain (ZNRF3ecto), a signalling-competent Furin1–Furin2 (Fu1–Fu2) fragment of Rspo2 (Rspo2Fu1–Fu2), and Rspo2Fu1–Fu2 in complex with ZNRF3ecto, or RNF43ecto. A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of RNF43ecto. Comparison of the four Rspo proteins, mutants and chimeras in biophysical and cellular assays shows that their signalling potency depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2.

Suggested Citation

  • Matthias Zebisch & Yang Xu & Christos Krastev & Bryan T. MacDonald & Maorong Chen & Robert J. C. Gilbert & Xi He & E. Yvonne Jones, 2013. "Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3787
    DOI: 10.1038/ncomms3787
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    Cited by:

    1. Lu Wang & Fangzheng Hu & Qianqian Cui & Huarui Qiao & Lingyun Li & Tengjie Geng & Yuying Li & Zengchao Sun & Siyu Zhou & Zhongyun Lan & Shaojue Guo & Ying Hu & Jiqiu Wang & Qilun Yang & Zenan Wang & Y, 2025. "Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    2. Hyeyoon Lee & Celine Marie Camuto & Christof Niehrs, 2024. "R-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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