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Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi

Author

Listed:
  • Xiaofeng Qi

    (University of Texas Southwestern Medical Center)

  • Heng Liu

    (University of Pittsburgh, School of Medicine)

  • Bonne Thompson

    (University of Texas Southwestern Medical Center)

  • Jeffrey McDonald

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

  • Cheng Zhang

    (University of Pittsburgh, School of Medicine)

  • Xiaochun Li

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

Abstract

The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway1,2. It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins3. Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class-A GPCR–Gi complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR.

Suggested Citation

  • Xiaofeng Qi & Heng Liu & Bonne Thompson & Jeffrey McDonald & Cheng Zhang & Xiaochun Li, 2019. "Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi," Nature, Nature, vol. 571(7764), pages 279-283, July.
    • Handle: RePEc:nat:nature:v:571:y:2019:i:7764:d:10.1038_s41586-019-1286-0
    DOI: 10.1038/s41586-019-1286-0
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    Cited by:

    1. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Xuan Zhang & Guibing Liu & Ya-Ni Zhong & Ru Zhang & Chuan-Cheng Yang & Canyang Niu & Xuanyu Pu & Jingjing Sun & Tianyao Zhang & Lejin Yang & Chao Zhang & Xiu Li & Xinyuan Shen & Peng Xiao & Jin-Peng S, 2024. "Structural basis of ligand recognition and activation of the histamine receptor family," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. 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.

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