G-protein-coupled Receptors in Fungi
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ABSTRACT:
SUBMITTER: Hesham A
PROVIDER: S-EPMC7302841 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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| S-EPMC3315628 | biostudies-literature
Project description:BackgroundG-protein coupled receptors (GPCRs) are the largest family of transmembrane receptors in fungi, where they play important roles in signal transduction. Among them, the Pth11-related GPCRs form a large and divergent protein family, and are only found in fungi in Pezizomycotina. However, the evolutionary process and potential functions of Pth11-related GPCRs remain largely unknown.ResultsTwenty genomes of fungi in Pezizomycotina covering different nutritional strategies were mined for putative Pth11-related GPCRs. Phytopathogens encode much more putative Pth11-related GPCRs than symbionts, saprophytes, or entomopathogens. Based on the phylogenetic tree, these GPCRs can be divided into nine clades, with each clade containing fungi in different taxonomic orders. Instead of fungi from the same order, those fungi with similar nutritional strategies were inclined to share orthologs of putative Pth11-related GPCRs. Most of the CFEM domain-containing Pth11-related GPCRs, which were only included in two clades, were detected in phytopathogens. Furthermore, many putative Pth11-related GPCR genes of phytopathogens were upregulated during invasive plant infection, but downregulated under biotic stress. The expressions of putative Pth11-related GPCR genes of saprophytes and entomopathogens could be affected by nutrient conditions, especially the carbon source. The gene expressions revealed that Pth11-related GPCRs could respond to biotic/abiotic stress and invasive plant infection with different expression patterns.ConclusionOur results indicated that the Pth11-related GPCRs existed before the diversification of Pezizomycotina and have been gained and/or lost several times during the evolutionary process. Tandem duplications and trophic variations have been important factors in this evolution.
| S-EPMC5526305 | biostudies-literature
Project description:Preparation and storage of functional membrane proteins such as G-protein-coupled receptors (GPCRs) are crucial to the processes of drug delivery and discovery. Here, we describe a method of preparing powdered GPCRs using rhodopsin as the prototype. We purified rhodopsin in CHAPS detergent with low detergent to protein ratio so the bulk of the sample represented protein (ca. 72% w/w). Our new method for generating powders of membrane proteins followed by rehydration paves the way for conducting functional and biophysical experiments. As an illustrative application, powdered rhodopsin was prepared with and without the cofactor 11-cis-retinal to enable partial rehydration of the protein with D2O in a controlled manner. Quasi-elastic neutron scattering studies using both spatial motion and energy landscape models form the basis for crucial insights into structural fluctuations and thermodynamics of GPCR activation.
| S-EPMC5386826 | biostudies-literature
Project description:Purpose of reviewClass A G protein-coupled receptors (GPCRs), including the chemokine receptors, CCR5 and CXCR4, share a seven transmembrane-spanning alpha-helix architecture that accommodates signal propagation from across biological membranes. CXCR4 and CCR5 are utilized as co-receptors during HIV viral entry and, therefore, crystal structures of GPCRs aid in the understanding of their function in viral entry.Recent findingsRecent progress in structure determination of class A GPCRs, which include vertebrate and invertebrate rhodopsin as well as adrenergic and adenosine receptors, provides molecular templates for how this diverse group of transmembrane receptors functions. Each of these GPCRs differs in how specific ligands bind to the transmembrane core, underscoring that additional structures of GPCRs from other subfamilies are needed to facilitate rational drug design. More recent studies also indicate a need to consider the more complex character of GPCRs, such as their oligomerization and dynamics.SummaryRecently, the atomic structures of invertebrate rhodopsin, beta1-adrenergic and beta2-adrenergic receptors and the A(2A)-adenosine receptor have been solved via X-ray crystallography. The impact that these structures have on the biochemistry of viral entry and signal transduction is discussed. Because the chemokine receptors have proven refractory to structural studies thus far, further structural study of the chemokine receptors will be essential to understanding ligand binding, activation and function as co-receptors during viral entry.
| S-EPMC2771364 | biostudies-literature
Project description:Oligomerization is one of several mechanisms that can regulate the activity of G protein-coupled receptors (GPCRs), but little is known about the structure of GPCR oligomers. Crystallography and NMR are the only methods able to reveal the details of receptor-receptor interactions at an atomic level, and several GPCR homodimers already have been described from crystal structures. Two clusters of symmetric interfaces have been identified from these structures that concur with biochemical data, one involving helices I, II, and VIII and the other formed mainly by helices V and VI. In this chapter, we describe the protocols used in our laboratory for the crystallization of rhodopsin and the ?2-adrenergic receptor (?2-AR). For bovine rhodopsin, we developed a new purification strategy including a (NH4)2SO4-induced phase separation that proved essential to obtain crystals of photoactivated rhodopsin containing parallel dimers. Crystallization of native bovine rhodopsin was achieved by the classic vapor-diffusion technique. For ?2-AR, we developed a purification strategy based on previously published protocols employing a lipidic cubic phase to obtain diffracting crystals of a ?2-AR/T4-lysozyme chimera bound to the antagonist carazolol.
| S-EPMC4605854 | biostudies-literature
Project description:Osteoarthritis (OA) is the most common chronic joint disease characterized, for which there are no available therapies being able to modify the progression of OA and prevent long-term disability. Critical roles of G-protein coupled receptors (GPCRs) have been established in OA cartilage degeneration, subchondral bone sclerosis and chronic pain. In this review, we describe the pathophysiological processes targeted by GPCRs in OA, along with related preclinical model and/or clinical trial data. We review examples of GPCRs which may offer attractive therapeutic strategies for OA, including receptors for cannabinoids, hormones, prostaglandins, fatty acids, adenosines, chemokines, and discuss the main challenges for developing these therapies.
| S-EPMC8831737 | biostudies-literature
Project description:G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.
| S-EPMC10757641 | biostudies-literature
Project description:The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.
| S-EPMC4322417 | biostudies-literature
Project description:G protein-coupled receptors (GPCRs) interact with three protein families following agonist binding: heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs) and arrestins. GRK-mediated phosphorylation of GPCRs promotes arrestin binding to uncouple the receptor from G protein, a process called desensitization, and for many GPCRs, arrestin binding also promotes receptor endocytosis and intracellular signaling. Thus, GRKs play a central role in modulating GPCR signaling and localization. Here we review recent advances in this field which include additional insight into how GRKs target GPCRs and bias signaling, and the development of specific inhibitors to dissect GRK function in model systems.
| S-EPMC7945687 | biostudies-literature
Project description:Cytokinesis, the last step during cell division, is a highly coordinated process that involves the relay of signals from both the outside and inside of the cell. We have a basic understanding of how cells regulate internal events, but how cells respond to extracellular cues is less explored. In a systematic RNAi screen of G protein-coupled receptors (GPCRs) and their effectors, we found that some GPCRs are involved in cytokinesis. RNAi knockdown of these GPCRs caused increased binucleated cell formation, and live cell imaging showed that most formed midbodies but failed at the abscission stage. OR2A4 (olfactory receptor, family 2, subfamily A, member 4) localized to cytokinetic structures in cells and its knockdown caused cytokinesis failure at an earlier stage, likely due to effects on the actin cytoskeleton. Identifying the downstream components that transmit GPCR signals during cytokinesis will be the next step and we show that GIPC1 (GIPC PDZ domain containing family, member 1), an adaptor protein for GPCRs, may play a part. RNAi knockdown of GIPC1 significantly increased binucleated cell formation. Understanding the molecular details of GPCRs and their interaction proteins in cytokinesis regulation will give us important clues about GPCRs signaling as well as how cells communicate with their environment during division.
| S-EPMC4137143 | biostudies-literature