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A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias.

ABSTRACT: Free Fatty Acid Receptor 2 is a GPCR activated by short chain fatty acids produced in high levels in the lower gut by microbial fermentation of non-digestible carbohydrates. A major challenge in studying this receptor is that the mouse ortholog does not have significant affinity for antagonists that are able to block the human receptor. Docking of exemplar antagonists from two chemical series to homology models of both human and mouse Free Fatty Acid Receptor 2 suggested that a single lysine - arginine variation at the extracellular face of the receptor might provide the basis for antagonist selectivity and mutational swap studies confirmed this hypothesis. Extending these studies to agonist function indicated that although the lysine - arginine variation between human and mouse orthologs had limited effect on G protein-mediated signal transduction, removal of positive charge from this residue produced a signalling-biased variant of Free Fatty Acid Receptor 2 in which Gi-mediated signalling by both short chain fatty acids and synthetic agonists was maintained whilst there was marked loss of agonist potency for signalling via Gq/11 and G12/13 G proteins. A single residue at the extracellular face of the receptor thus plays key roles in both agonist and antagonist function.

SUBMITTER: Sergeev E

PROVIDER: S-EPMC5653858 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias.

Sergeev Eugenia E Hansen Anders Højgaard AH Bolognini Daniele D Kawakami Kouki K Kishi Takayuki T Aoki Junken J Ulven Trond T Inoue Asuka A Hudson Brian D BD Milligan Graeme G

Scientific reports 20171023 1

Free Fatty Acid Receptor 2 is a GPCR activated by short chain fatty acids produced in high levels in the lower gut by microbial fermentation of non-digestible carbohydrates. A major challenge in studying this receptor is that the mouse ortholog does not have significant affinity for antagonists that are able to block the human receptor. Docking of exemplar antagonists from two chemical series to homology models of both human and mouse Free Fatty Acid Receptor 2 suggested that a single lysine - a ...[more]

PMID: 29061999

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Project description:Gene transfer agents (GTAs) are virus-like elements integrated into bacterial genomes, particularly, those of Alphaproteobacteria The GTAs can be induced under conditions of nutritional stress, incorporate random fragments of bacterial DNA into miniphage particles, lyse the host cells, and infect neighboring bacteria, thus enhancing horizontal gene transfer. We show that GTA genes evolve under conditions of pronounced positive selection for the reduction of the energy cost of protein production as shown by comparison of the amino acid compositions with those of both homologous viral genes and host genes. The energy saving in GTA genes is comparable to or even more pronounced than that in the genes encoding the most abundant, essential bacterial proteins. In cases in which viruses acquire genes from GTAs, the bias in amino acid composition disappears in the course of evolution, showing that reduction of the energy cost of protein production is an important factor of evolution of GTAs but not bacterial viruses. These findings strongly suggest that GTAs represent bacterial adaptations rather than selfish, virus-like elements. Because GTA production kills the host cell and does not propagate the GTA genome, it appears likely that the GTAs are retained in the course of evolution via kin or group selection. Therefore, we hypothesize that GTAs facilitate the survival of bacterial populations under energy-limiting conditions through the spread of metabolic and transport capabilities via horizontal gene transfer and increases in nutrient availability resulting from the altruistic suicide of GTA-producing cells.IMPORTANCE Kin selection and group selection remain controversial topics in evolutionary biology. We argue that these types of selection are likely to operate in bacterial populations by showing that bacterial gene transfer agents (GTAs), but not related viruses, evolve under conditions of positive selection for the reduction of the energy cost of GTA particle production. We hypothesize that GTAs are dedicated devices mediating the survival of bacteria under conditions of nutrient limitation. The benefits conferred by GTAs under nutritional stress conditions appear to include horizontal dissemination of genes that could provide bacteria with enhanced capabilities for nutrient utilization and increases of nutrient availability occurring through the lysis of GTA-producing bacteria.

Dataset Information

A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias.

Publications

A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias.

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