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Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling

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Listed:
  • Samuel C. Griffiths

    (University of Oxford
    Evotec (UK) Ltd., Milton Park)

  • Rebekka A. Schwab

    (University of Oxford)

  • Kamel El Omari

    (Science Division, Diamond Light Source, Harwell Science and Innovation Campus)

  • Benjamin Bishop

    (University of Oxford)

  • Ellen J. Iverson

    (Stanford University School of Medicine)

  • Tomas Malinauskas

    (University of Oxford)

  • Ramin Dubey

    (Stanford University School of Medicine)

  • Mingxing Qian

    (Washington University School of Medicine)

  • Douglas F. Covey

    (Washington University School of Medicine)

  • Robert J. C. Gilbert

    (University of Oxford)

  • Rajat Rohatgi

    (Stanford University School of Medicine)

  • Christian Siebold

    (University of Oxford)

Abstract

Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling.

Suggested Citation

  • Samuel C. Griffiths & Rebekka A. Schwab & Kamel El Omari & Benjamin Bishop & Ellen J. Iverson & Tomas Malinauskas & Ramin Dubey & Mingxing Qian & Douglas F. Covey & Robert J. C. Gilbert & Rajat Rohatg, 2021. "Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27475-2
    DOI: 10.1038/s41467-021-27475-2
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    References listed on IDEAS

    as
    1. Pao-Tien Chuang & Andrew P. McMahon, 1999. "Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein," Nature, Nature, vol. 397(6720), pages 617-621, February.
    2. Jason S. McLellan & Xiaoyan Zheng & Glenn Hauk & Rodolfo Ghirlando & Philip A. Beachy & Daniel J. Leahy, 2008. "The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla," Nature, Nature, vol. 455(7215), pages 979-983, October.
    3. Xiaofeng Qi & Philip Schmiege & Elias Coutavas & Jiawei Wang & Xiaochun Li, 2018. "Structures of human Patched and its complex with native palmitoylated sonic hedgehog," Nature, Nature, vol. 560(7716), pages 128-132, August.
    4. Chen Chen & Jiyuan Ke & X. Edward Zhou & Wei Yi & Joseph S. Brunzelle & Jun Li & Eu-Leong Yong & H. Eric Xu & Karsten Melcher, 2013. "Structural basis for molecular recognition of folic acid by folate receptors," Nature, Nature, vol. 500(7463), pages 486-489, August.
    5. Lina Kwong & Maarten F. Bijlsma & Henk Roelink, 2014. "Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
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