The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors

Abstract

The β-arrestins (βarrs) are versatile, multifunctional adapter proteins that are best known for their ability to desensitize G protein-coupled receptors (GPCRs), but also regulate a diverse array of cellular functions. To signal in such a complex fashion, βarrs adopt multiple conformations and are regulated at multiple levels to differentially activate downstream pathways. Recent structural studies have demonstrated that βarrs have a conserved structure and activation mechanism, with plasticity of their structural fold, allowing them to adopt a wide array of conformations. Novel roles for βarrs continue to be identified, demonstrating the importance of these dynamic regulators of cellular signaling.

Keywords: 7-helix receptor; G protein-coupled receptor (GPCR); arrestin; receptor desensitization; receptor endocytosis; signaling.

FIGURE 1.

The spectrum of βarr-mediated signaling. βarrs regulate a wide array of pathways downstream of GPCRs (see text). PDEs, phosphodiesterases; EGFR, EGF receptor; PP2A, protein phosphatase 2A; TRP, transient receptor potential.

FIGURE 2.

Balanced and biased signaling by GPCRs. Top panel, in balanced signaling, both G protein-mediated and βarr-mediated signaling pathways are activated by the ligand·receptor complex. Bottom panel, in G protein- or βarr-biased signaling, one of the pathways is activated while the other pathway is blocked.

FIGURE 3.

Regulation of βarrs by GPCR signaling barcodes. A–C, in the signaling barcode model, a receptor activated by ligand (A) recruits kinases and other enzymes that generate a signaling barcode (B) on the C-terminal tail of the receptor. This results in the recruitment of βarr and activation of effector molecules (C). D, changes to the barcode result in differential effector coupling by βarrs (shown are the clathrin adapter AP-2 and ERK MAPK). 7TMR, seven-transmembrane class of receptors; Ub, ubiquitin.

FIGURE 4.

Structural mechanisms for βarr activation and signaling. A, βarractivation occurs through disruption of the polar core (“phosphate sensor”) by the phosphorylated C terminus of the receptor, thereby allowing specific motifs in βarr (“activation sensor,” including the finger and lariat loops) to bind to the ligand-activated receptor (inactive structure, Protein Data Bank (PDB) 1G4M; active structure, PDB 4JQI). B, alternative models for the finger loop interaction from the rhodopsin·finger loop peptide structure (yellow, PDB 4PXF) and the rhodopsin·arrestin-1 structure (cyan, PDB 4ZWJ) with the active receptor (green). C, single particle electron microscopy identifies distinct conformations of β2AR·βarr, with a tail conformation with interactions between the C-terminal tail of the receptor with βarr (phosphate sensor only) and a core conformation with interactions between the transmembrane domains and βarrs (activation sensor and phosphate sensor). EM images courtesy of Thomas Cahill.