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Smoothened stimulation by membrane sterols drives Hedgehog pathway activity

Author

Listed:
  • Ishan Deshpande

    (University of California, San Francisco)

  • Jiahao Liang

    (University of California, San Francisco)

  • Danielle Hedeen

    (University of Utah School of Medicine
    University of Utah School of Medicine)

  • Kelsey J. Roberts

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Yunxiao Zhang

    (Stanford University School of Medicine)

  • Betty Ha

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Naomi R. Latorraca

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Bryan Faust

    (University of California, San Francisco)

  • Ron O. Dror

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Philip A. Beachy

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Benjamin R. Myers

    (Stanford University School of Medicine
    University of Utah School of Medicine
    University of Utah School of Medicine)

  • Aashish Manglik

    (University of California, San Francisco
    University of California, San Francisco)

Abstract

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration1. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma2. Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models3–5, a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results—combined with signalling studies and molecular dynamics simulations—delineate the structural basis for PTCH1–SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.

Suggested Citation

  • Ishan Deshpande & Jiahao Liang & Danielle Hedeen & Kelsey J. Roberts & Yunxiao Zhang & Betty Ha & Naomi R. Latorraca & Bryan Faust & Ron O. Dror & Philip A. Beachy & Benjamin R. Myers & Aashish Mangli, 2019. "Smoothened stimulation by membrane sterols drives Hedgehog pathway activity," Nature, Nature, vol. 571(7764), pages 284-288, July.
  • Handle: RePEc:nat:nature:v:571:y:2019:i:7764:d:10.1038_s41586-019-1355-4
    DOI: 10.1038/s41586-019-1355-4
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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. Atanu Maiti & Cosmo Z. Buffalo & Saumya Saurabh & Felipe Montecinos-Franjola & Justin S. Hachey & William J. Conlon & Geraldine N. Tran & Bakar Hassan & Kylie J. Walters & Mikhail Drobizhev & W. E. Mo, 2023. "Structural and photophysical characterization of the small ultra-red fluorescent protein," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. L. Paige Ferguson & Jovylyn Gatchalian & Matthew L. McDermott & Mari Nakamura & Kendall Chambers & Nirakar Rajbhandari & Nikki K. Lytle & Sara Brin Rosenthal & Michael Hamilton & Sonia Albini & Martin, 2023. "Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Yanying Wang & Jing Wang & Xiaoyu Li & Xushen Xiong & Jianyi Wang & Ziheng Zhou & Xiaoxiao Zhu & Yang Gu & Dan Dominissini & Lei He & Yong Tian & Chengqi Yi & Zusen Fan, 2021. "N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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