title: 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.
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Moutusi
authors.identifier: 0000-0001-9472-1594
authors.initials: M
authors.lastname: Manna
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Miia
authors.initials: M
authors.lastname: Niemelä
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Joona
authors.initials: J
authors.lastname: Tynkkynen
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, University of Helsinki, Helsinki, Finland.
authors.forename: Matti
authors.identifier: 0000-0003-4858-364X
authors.initials: M
authors.lastname: Javanainen
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, University of Helsinki, Helsinki, Finland.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kulig
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, University of Helsinki, Helsinki, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rog
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.|Department of Physics, University of Helsinki, Helsinki, Finland.|MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.
authors.forename: Ilpo
authors.identifier: 0000-0001-7408-3214
authors.initials: I
authors.lastname: Vattulainen
mesh_terms: D000494:Allosteric Regulation; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018343:Receptors, Adrenergic, beta-2; D002784:Cholesterol
keywords: allosteric regulation; biophysics; cholesterol; computational biology; human; lipid-protein interactions; membrane receptor; molecular dynamics simulation; structural biology; systems biology