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Emerging structural insights into GPCR-β-arrestin interaction and functional outcomes.

ABSTRACT: Agonist-induced recruitment of β-arrestins (βarrs) to G protein-coupled receptors (GPCRs) plays a central role in regulating the spatio-temporal aspects of GPCR signaling. Several recent studies have provided novel structural and functional insights into our understanding of GPCR-βarr interaction, subsequent βarr activation and resulting functional outcomes. In this review, we discuss these recent advances with a particular emphasis on recognition of receptor-bound phosphates by βarrs, the emerging concept of spatial positioning of key phosphorylation sites, the conformational transition in βarrs during partial to full-engagement, and structural differences driving functional outcomes of βarr isoforms. We also highlight the key directions that require further investigation going forward to fully understand the structural mechanisms driving βarr activation and functional responses.

SUBMITTER: Maharana J

PROVIDER: S-EPMC7614528 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Emerging structural insights into GPCR-β-arrestin interaction and functional outcomes.

Maharana Jagannath J Banerjee Ramanuj R Yadav Manish K MK Sarma Parishmita P Shukla Arun K AK

Current opinion in structural biology 20220620

Agonist-induced recruitment of β-arrestins (βarrs) to G protein-coupled receptors (GPCRs) plays a central role in regulating the spatio-temporal aspects of GPCR signaling. Several recent studies have provided novel structural and functional insights into our understanding of GPCR-βarr interaction, subsequent βarr activation and resulting functional outcomes. In this review, we discuss these recent advances with a particular emphasis on recognition of receptor-bound phosphates by βarrs, the emerg ...[more]

PMID: 35738165

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Project description:β-arrestins regulate many cellular functions including intracellular signaling and desensitization of G protein-coupled receptors (GPCRs). Previous studies show that β-arrestin signaling and receptor endocytosis are modulated by the plasma membrane phosphoinositide lipid phosphatidylinositol-(4, 5)-bisphosphate (PI(4,5)P2). We found that β-arrestin also helped promote synthesis of PI(4,5)P2 and up-regulated GPCR endocytosis. We studied these questions with the Gq-coupled protease-activated receptor 2 (PAR2), which activates phospholipase C, desensitizes quickly, and undergoes extensive endocytosis. Phosphoinositides were monitored and controlled in live cells using lipid-specific fluorescent probes and genetic tools. Applying PAR2 agonist initiated depletion of PI(4,5)P2, which then recovered during rapid receptor desensitization, giving way to endocytosis. This endocytosis could be reduced by various manipulations that depleted phosphoinositides again right after phosphoinositide recovery: PI(4)P, a precusor of PI(4,5)P2, could be depleted at either the Golgi or the plasma membrane (PM) using a recruitable lipid 4-phosphatase enzyme and PI(4,5)P2 could be depleted at the PM using a recruitable 5-phosphatase. Endocytosis required the phosphoinositides. Knock-down of β-arrestin revealed that endogenous β-arrestin normally doubles the rate of PIP5-kinase (PIP5K) after PAR2 desensitization, boosting PI(4,5)P2-dependent formation of clathrin-coated pits (CCPs) at the PM. Desensitized PAR2 receptors were swiftly immobilized when they encountered CCPs, showing a dwell time of ∼90 s, 100 times longer than for unactivated receptors. PAR2/β-arrestin complexes eventually accumulated around the edges or across the surface of CCPs promoting transient binding of PIP5K-Iγ. Taken together, β-arrestins can coordinate potentiation of PIP5K activity at CCPs to induce local PI(4,5)P2 generation that promotes recruitment of PI(4,5)P2-dependent endocytic machinery.

Dataset Information

Emerging structural insights into GPCR-β-arrestin interaction and functional outcomes.

Publications

Emerging structural insights into GPCR-β-arrestin interaction and functional outcomes.

Similar Datasets

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