Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor

Nat Commun. 2023 Apr 10;14(1):2005. doi: 10.1038/s41467-023-37233-1.


Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The β2 adrenergic receptor's (β2AR) 71 amino acid CT is a substrate for GPCR kinases and binds β-arrestins to regulate signaling. Here we show that the β2AR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking β-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged β2AR-CT serves as an autoinhibitory factor via interacting with the positively charged cytoplasmic surface of the receptor to limit access to G-proteins. The stability of this interaction is influenced by agonists and allosteric modulators, emphasizing that the CT plays important role in allosterically regulating GPCR activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Receptors, Adrenergic / metabolism
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, G-Protein-Coupled* / metabolism
  • Signal Transduction*
  • beta-Arrestins / metabolism


  • beta-Arrestins
  • Receptors, G-Protein-Coupled
  • Receptors, Adrenergic
  • Receptors, Adrenergic, beta-2