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Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol
Journal article

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

  • Manna, Moutusi ORCID Department of Physics, Tampere University of Technology, Tampere, Finland
  • Niemelä, Miia Department of Physics, Tampere University of Technology, Tampere, Finland
  • Tynkkynen, Joona Department of Physics, Tampere University of Technology, Tampere, Finland
  • Javanainen, Matti ORCID Department of Physics, University of Helsinki, Helsinki, Finland
  • Kulig, Waldemar Department of Physics, University of Helsinki, Helsinki, Finland
  • Müller, Daniel J Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
  • Rog, Tomasz Department of Physics, University of Helsinki, Helsinki, Finland
  • Vattulainen, Ilpo ORCID MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark
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  • 2016-11-29
Published in:
  • eLife. - eLife Sciences Publications, Ltd. - 2016, vol. 5
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/139745
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