Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Proteins known as G protein-coupled receptors, or GPCRs for short, detect and respond to hormones and other signaling molecules found outside cells. A signaling molecule activates a GPCR by binding to it and causing the receptor to change its shape. This triggers a cascade of signals inside the cell that leads to the cell responding in a particular way. There are over 800 different GPCRs in human cells, making them the largest family of cell surface proteins.

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.

Read more: