IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v4y2013i1d10.1038_ncomms3787.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms3787
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms3787?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3787. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.