1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology
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Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

  1. Moutusi Manna
  2. Miia Niemelä
  3. Joona Tynkkynen
  4. Matti Javanainen
  5. Waldemar Kulig
  6. Daniel J Müller
  7. Tomasz Rog
  8. Ilpo Vattulainen  Is a corresponding author
  1. Tampere University of Technology, Finland
  2. ETH Zürich, Switzerland
Research Article
  • Cited 37
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Cite this article as: eLife 2016;5:e18432 doi: 10.7554/eLife.18432

Abstract

There is evidence that lipids can be allosteric regulators of membrane protein structure and activation. However, there are no data showing how exactly the regulation emerges from specific lipid-protein interactions. Here we show in atomistic detail how the human β2-adrenergic receptor (β2AR) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates β2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located near the transmembrane helices 5-7 of the receptor. The alternative mechanism, where the β2AR conformation would be modulated by membrane-mediated interactions, plays only a minor role. Cholesterol analogues also bind to cholesterol binding sites and impede the structural flexibility of β2AR, however cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions.

Article and author information

Author details

  1. Moutusi Manna

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  2. Miia Niemelä

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  3. Joona Tynkkynen

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  4. Matti Javanainen

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4858-364X
  5. Waldemar Kulig

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel J Müller

    Department of Biosystems Science and Engineering, ETH Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Tomasz Rog

    Department of Physics, Tampere University of Technology, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Ilpo Vattulainen

    Department of Physics, Tampere University of Technology, Tampere, Finland
    For correspondence
    Ilpo.Vattulainen@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7408-3214

Funding

European Research Council (290974)

  • Moutusi Manna
  • Waldemar Kulig
  • Tomasz Rog
  • Ilpo Vattulainen

Academy of Finland (272130)

  • Moutusi Manna
  • Joona Tynkkynen
  • Matti Javanainen
  • Waldemar Kulig
  • Tomasz Rog
  • Ilpo Vattulainen

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

Reviewing Editor

  1. Nir Ben-Tal, Tel Aviv University, Israel

Publication history

  1. Received: June 2, 2016
  2. Accepted: November 28, 2016
  3. Accepted Manuscript published: November 29, 2016 (version 1)
  4. Version of Record published: December 30, 2016 (version 2)

Copyright

© 2016, Manna 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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