IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v571y2019i7764d10.1038_s41586-019-1286-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1286-0
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-019-1286-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:571:y:2019:i:7764:d:10.1038_s41586-019-1286-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.