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Structures of human Patched and its complex with native palmitoylated sonic hedgehog

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  • Xiaofeng Qi

    (University of Texas Southwestern Medical Center)

  • Philip Schmiege

    (University of Texas Southwestern Medical Center)

  • Elias Coutavas

    (The Rockefeller University)

  • Jiawei Wang

    (School of Life Sciences, Tsinghua University)

  • Xiaochun Li

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1–3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4–6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of ‘native’ sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann–Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1–SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH-N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7716:d:10.1038_s41586-018-0308-7
    DOI: 10.1038/s41586-018-0308-7
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    Cited by:

    1. Megan Lo & Amnon Sharir & Michael D. Paul & Hayarpi Torosyan & Christopher Agnew & Amy Li & Cynthia Neben & Pauline Marangoni & Libin Xu & David R. Raleigh & Natalia Jura & Ophir D. Klein, 2022. "CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Wanqiu Li & Linlin Wang & Bradley M. Wierbowski & Mo Lu & Feitong Dong & Wenchen Liu & Sisi Li & Peiyi Wang & Adrian Salic & Xin Gong, 2021. "Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Hongwen Chen & Xiaofeng Qi & Rebecca A. Faulkner & Marc M. Schumacher & Linda M. Donnelly & Russell A. DeBose-Boyd & Xiaochun Li, 2022. "Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.

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