Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol
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
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
- Nir Ben-Tal, Tel Aviv University, Israel
Version history
- Received: June 2, 2016
- Accepted: November 28, 2016
- Accepted Manuscript published: November 29, 2016 (version 1)
- 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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