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Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm

Author

Listed:
  • Hongwu Qian

    (Princeton University)

  • Pingping Cao

    (Tsinghua University)

  • Miaohui Hu

    (Princeton University)

  • Shuai Gao

    (Princeton University)

  • Nieng Yan

    (Princeton University)

  • Xin Gong

    (Princeton University
    Southern University of Science and Technology)

Abstract

The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhNp through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhNp and the other through the Ca2+-mediated interface on ShhNp. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.

Suggested Citation

  • Hongwu Qian & Pingping Cao & Miaohui Hu & Shuai Gao & Nieng Yan & Xin Gong, 2019. "Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10234-9
    DOI: 10.1038/s41467-019-10234-9
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    Cited by:

    1. Roman Vetter & Dagmar Iber, 2022. "Precision of morphogen gradients in neural tube development," Nature Communications, Nature, vol. 13(1), pages 1-14, 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. Yidan Xu & Guowen Jia & Tingting Li & Zixuan Zhou & Yitian Luo & Yulin Chao & Juan Bao & Zhaoming Su & Qianhui Qu & Dianfan Li, 2022. "Molecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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