ArticleThe Journal of biological chemistry2014
Concomitant action of structural elements and receptor phosphorylation determines arrestin-3 interaction with the free fatty acid receptor FFA4.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 62 citations in OpenAlex.
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner.Communications biology · 2025Article
- Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120).Pharmacology & therapeutics · 2025Review
- Middle-Down Mass Spectrometry Reveals Activity-Modifying Phosphorylation Barcode in a Class C G Protein-Coupled Receptor.Journal of the American Chemical Society · 2022Article
- How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors.International journal of molecular sciences · 2022Review
- Accelerated Multiphosphorylated Peptide Synthesis.Organic process research & development · 2022Review
- Delineating the interactions between the cannabinoid CBBritish journal of pharmacology · 2022Article
- Selective phosphorylation of threonine residues defines GPR84-arrestin interactions of biased ligands.The Journal of biological chemistry · 2022Article
- Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations.Computational and structural biotechnology journal · 2021Article
- Carboxy-Terminal Phosphoregulation of the Long Splice Isoform of Free-Fatty Acid Receptor-4 MediatesMolecular pharmacology · 2020Article
- Updates in the function and regulation of αBritish journal of pharmacology · 2019Review
- S1PBioscience reports · 2018Article
- The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines.Biochemical pharmacology · 2018Review
- Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.Biochemical pharmacology · 2017Article
- FFA4/GPR120: Pharmacology and Therapeutic Opportunities.Trends in pharmacological sciences · 2017Review
- Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks.Cellular signalling · 2017Review
- Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4.Molecular pharmacology · 2017Article
- Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling.The Journal of biological chemistry · 2016Article
- Novel Structural Approaches to Study GPCR Regulation.International journal of molecular sciences · 2016Review
- Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling.The Biochemical journal · 2016Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
In addition to being nutrients, free fatty acids act as signaling molecules by activating a family of G protein-coupled receptors. Among these is FFA4, previously called GPR120, which responds to medium and long chain fatty acids, including health-promoting ω-3 fatty acids, which have been implicated in the regulation of metabolic and inflammatory responses. Here we show, using mass spectrometry, mutagenesis, and phosphospecific antibodies, that agonist-regulated phosphorylation of the human FFA4 receptor occurred primarily at five residues (Thr(347), Thr(349), Ser(350), Ser(357), and Ser(360)) in the C-terminal tail. Mutation of these residues reduced both the efficacy and potency of ligand-mediated arrestin-3 recruitment as well as affecting recruitment kinetics. Combined mutagenesis of all five of these residues was insufficient to fully abrogate interaction with arrestin-3, but further mutagenesis of negatively charged residues revealed additional structural components for the interaction with arrestin-3 within the C-terminal tail of the receptor. These elements consist of the acidic residues Glu(341), Asp(348), and Asp(355) located close to the phosphorylation sites. Receptor phosphorylation thus operates in concert with structural elements within the C-terminal tail of FFA4 to allow for the recruitment of arrestin-3. Importantly, these mechanisms of arrestin-3 recruitment operate independently from Gq/11 coupling, thereby offering the possibility that ligands showing stimulus bias could be developed that exploit these differential coupling mechanisms. Furthermore, this provides a strategy for the design of biased receptors to probe physiologically relevant signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.