Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

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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.

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Moutusi Manna

Department of Physics, Tampere University of Technology, Tampere, Finland

Competing interests
The authors declare that no competing interests exist.
Miia Niemelä

Department of Physics, Tampere University of Technology, Tampere, Finland

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The authors declare that no competing interests exist.
Joona Tynkkynen

Department of Physics, Tampere University of Technology, Tampere, Finland

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The authors declare that no competing interests exist.
Matti Javanainen

Department of Physics, Tampere University of Technology, Tampere, Finland

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4858-364X
Waldemar Kulig

Department of Physics, Tampere University of Technology, Tampere, Finland

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The authors declare that no competing interests exist.
Daniel J Müller

Department of Biosystems Science and Engineering, ETH Zürich, Zürich, Switzerland

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The authors declare that no competing interests exist.
Tomasz Rog

Department of Physics, Tampere University of Technology, Tampere, Finland

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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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.