Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling

  1. Giovanni Luchetti
  2. Ria Sircar
  3. Jennifer H Kong
  4. Sigrid Nachtergaele
  5. Andreas Sagner
  6. Eamon FX Byrne
  7. Douglas F Covey
  8. Christian Siebold  Is a corresponding author
  9. Rajat Rohatgi  Is a corresponding author
  1. Stanford University School of Medicine, United States
  2. The Francis Crick Institute, United Kingdom
  3. University of Oxford, United Kingdom
  4. Washington University School of Medicine, United States

Abstract

Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike most GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.

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Author details

  1. Giovanni Luchetti

    Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ria Sircar

    Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer H Kong

    Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sigrid Nachtergaele

    Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Andreas Sagner

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Eamon FX Byrne

    Division of Structural Biology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Douglas F Covey

    Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christian Siebold

    Division of Structural Biology, University of Oxford, Oxford, United Kingdom
    For correspondence
    christian@strubi.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6635-3621
  9. Rajat Rohatgi

    Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, United States
    For correspondence
    rrohatgi@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7609-8858

Funding

National Institutes of Health (GM106078, HL067773)

  • Douglas F Covey
  • Rajat Rohatgi

Cancer Research UK (C20724/A14414)

  • Christian Siebold

Taylor Family institute for Psychiatric Research

  • Douglas F Covey

Ford Foundation

  • Giovanni Luchetti

National Science Foundation

  • Sigrid Nachtergaele

Nuffield Department of Medicine, Oxford University

  • Eamon FX Byrne

EMBO LTF (1438-2013)

  • Andreas Sagner

HFSP LTF (LT000401/2014-L)

  • Andreas Sagner

People Programme of the EU's Seventh Framework Programme (FP7-2013)

  • Andreas Sagner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Duojia Pan, UT Southwestern Medical Center, United States

Version history

  1. Received: August 5, 2016
  2. Accepted: October 3, 2016
  3. Accepted Manuscript published: October 5, 2016 (version 1)
  4. Version of Record published: November 25, 2016 (version 2)

Copyright

© 2016, Luchetti et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Giovanni Luchetti
  2. Ria Sircar
  3. Jennifer H Kong
  4. Sigrid Nachtergaele
  5. Andreas Sagner
  6. Eamon FX Byrne
  7. Douglas F Covey
  8. Christian Siebold
  9. Rajat Rohatgi
(2016)
Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
eLife 5:e20304.
https://doi.org/10.7554/eLife.20304

Share this article

https://doi.org/10.7554/eLife.20304

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