Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol
Manna, Moutusi; Niemelä, Miia; Tynkkynen, Joona; Javanainen, Matti; Kulig, Waldemar; Müller, Daniel J; Rog, Tomasz; Vattulainen, Ilpo (2016-11-29)
Manna, Moutusi
Niemelä, Miia
Tynkkynen, Joona
Javanainen, Matti
Kulig, Waldemar
Müller, Daniel J
Rog, Tomasz
Vattulainen, Ilpo
29.11.2016
e18432
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tty-201612224911
https://urn.fi/URN:NBN:fi:tty-201612224911
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [16944]