Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin.
Kelly N. Nobles,Kunhong Xiao,Seungkirl Ahn,Arun K. Shukla,Arun K. Shukla,Christopher M. Lam,Sudarshan Rajagopal,Ryan T. Strachan,Teng Yi Huang,Erin Ashley Bressler,Makoto R. Hara,Sudha K. Shenoy,Steven P. Gygi,Robert J. Lefkowitz,Robert J. Lefkowitz +14 more
TLDR
It is proposed that the distinct phosphorylation patterns established by different GRKs establish a “barcode” that imparts distinct conformations to the recruited β-arrestin, thus regulating its functional activities.Abstract:
Phosphorylation of G protein–coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arrestins. These multifunctional adaptor proteins desensitize GPCRs, by reducing receptor coupling to G proteins and facilitating receptor internalization, and mediate GPCR signaling through β-arrestin–specific pathways. Detailed mapping of the phosphorylation sites on GPCRs targeted by individual GRKs and an understanding of how these sites regulate the specific functional consequences of β-arrestin engagement may aid in the discovery of therapeutic agents targeting individual β-arrestin functions. The β 2 -adrenergic receptor (β 2 AR) has many serine and threonine residues in the carboxyl-terminal tail and the intracellular loops, which are potential sites of phosphorylation. We monitored the phosphorylation of the β 2 AR at specific sites upon stimulation with an agonist that promotes signaling by both G protein–mediated and β-arrestin–mediated pathways or with a biased ligand that promotes signaling only through β-arrestin–mediated events in the presence of the full complement of GRKs or when either GRK2 or GRK6 was depleted. We correlated the specific and distinct patterns of receptor phosphorylation by individual GRKs with the functions of β-arrestins and propose that the distinct phosphorylation patterns established by different GRKs establish a “barcode” that imparts distinct conformations to the recruited β-arrestin, thus regulating its functional activities.read more
Citations
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Molecular signatures of G-protein-coupled receptors.
AJ Venkatakrishnan,Xavier Deupi,Guillaume Lebon,Christopher G. Tate,Gebhard F. X. Schertler,Gebhard F. X. Schertler,M. Madan Babu +6 more
TL;DR: Through a systematic analysis of high-resolution GPCR structures, a conserved network of non-covalent contacts that defines the G PCR fold is uncovered and characteristic features of ligand binding and conformational changes during receptor activation are revealed.
Journal ArticleDOI
Structure-Function of the G Protein–Coupled Receptor Superfamily
TL;DR: High-resolution crystallography of G protein-coupled receptors shows the receptors as allosteric machines that are controlled not only by ligands but also by ions, lipids, cholesterol, and water, and helps redefine knowledge of how GPCRs recognize such a diverse array of ligands.
Journal ArticleDOI
Biased Signaling Pathways in β2-Adrenergic Receptor Characterized by 19F-NMR
TL;DR: 19F-NMR spectroscopy was used to examine conformational changes associated with a range of ligands and discovered that biased ligands caused differential shifts in equilibrium between two conformational states—the G protein binding state and the arrestin binding state—and thus provide a basis for rational design of pharmacological ligands.
Journal ArticleDOI
Structure and dynamics of GPCR signaling complexes
TL;DR: Current insights into the structural plasticity of G PCR–G-protein and GPCR–arrestin complexes that underlies the regulation of the receptor’s intracellular signaling profile are summarized.
Journal ArticleDOI
Molecular Mechanism of β-Arrestin-Biased Agonism at Seven-Transmembrane Receptors
TL;DR: One particular class of biased ligands has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects.
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