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Science (New York, N.Y.) Jan 2022GPR158 is an orphan G protein–coupled receptor (GPCR) highly expressed in the brain, where it controls synapse formation and function. GPR158 has also been implicated...
GPR158 is an orphan G protein–coupled receptor (GPCR) highly expressed in the brain, where it controls synapse formation and function. GPR158 has also been implicated in depression, carcinogenesis, and cognition. However, the structural organization and signaling mechanisms of GPR158 are largely unknown. We used single-particle cryo–electron microscopy (cryo-EM) to determine the structures of human GPR158 alone and bound to an RGS signaling complex. The structures reveal a homodimeric organization stabilized by a pair of phospholipids and the presence of an extracellular Cache domain, an unusual ligand-binding domain in GPCRs. We further demonstrate the structural basis of GPR158 coupling to RGS7-Gβ5. Together, these results provide insights into the unusual biology of orphan receptors and the formation of GPCR-RGS complexes.
Topics: Binding Sites; Cryoelectron Microscopy; GTP-Binding Protein beta Subunits; Humans; Ligands; Models, Molecular; Phospholipids; Protein Binding; Protein Conformation; Protein Conformation, alpha-Helical; Protein Domains; Protein Multimerization; Protein Subunits; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34793198
DOI: 10.1126/science.abl4732 -
Science (New York, N.Y.) Oct 2021Recently reported to be effective in patients with lung cancer, KRAS inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein...
Recently reported to be effective in patients with lung cancer, KRAS inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS hydrolyzes sufficient GTP to allow inactive state–selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein–coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.
Topics: Animals; Cell Extracts; Cell Line, Tumor; Enzyme Activation; GTP Phosphohydrolases; Guanosine Triphosphate; Humans; Hydrolysis; Lung Neoplasms; Mice, Nude; Proto-Oncogene Proteins p21(ras); RGS Proteins; Signal Transduction; Xenograft Model Antitumor Assays; Mice
PubMed: 34618566
DOI: 10.1126/science.abf1730 -
International Journal of Molecular... Mar 2023The regulator of G protein signaling (RGS) proteins are crucial for the termination of G protein signals elicited by G protein-coupled receptors (GPCRs). This... (Review)
Review
The regulator of G protein signaling (RGS) proteins are crucial for the termination of G protein signals elicited by G protein-coupled receptors (GPCRs). This superfamily of cell membrane receptors, by far the largest and most versatile in mammals, including humans, play pivotal roles in the regulation of cardiac function and homeostasis. Perturbations in both the activation and termination of their G protein-mediated signaling underlie numerous heart pathologies, including heart failure (HF) and atrial fibrillation (AFib). Therefore, RGS proteins play important roles in the pathophysiology of these two devasting cardiac diseases, and several of them could be targeted therapeutically. Although close to 40 human RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type. Numerous in vitro and in vivo studies in animal models, and also in diseased human heart tissue obtained from transplantations or tissue banks, have provided substantial evidence of the roles various cardiomyocyte RGS proteins play in cardiac normal homeostasis as well as pathophysiology. One RGS protein in particular, RGS4, has been reported in what are now decades-old studies to be selectively upregulated in human HF. It has also been implicated in protection against AFib via knockout mice studies. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of HF and AFib, with a specific focus on RGS4 for the aforementioned reasons but also because it can be targeted successfully with small organic molecule inhibitors.
Topics: Animals; Humans; Mice; Atrial Fibrillation; GTP-Binding Proteins; Heart Failure; Mammals; RGS Proteins; Signal Transduction
PubMed: 37047106
DOI: 10.3390/ijms24076136 -
The AAPS Journal Mar 2016G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the... (Review)
Review
G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the host responses to pathogens through direct recognition of secreted microbial products or the by-products of host cells damaged by pathogen exposure. In the mid-1990s, a large group of intracellular proteins was discovered, the regulator of G protein signaling (RGS) family, whose main, but not exclusive, function appears to be to constrain the intensity and duration of GPCR signaling. The R4/B subfamily--the focus of this review--includes RGS1-5, 8, 13, 16, 18, and 21, which are the smallest RGS proteins in size, with the exception of RGS3. Prominent roles in the trafficking of B and T lymphocytes and macrophages have been described for RGS1, RGS13, and RGS16, while RGS18 appears to control platelet and osteoclast functions. Additional G protein independent functions of RGS13 have been uncovered in gene expression in B lymphocytes and mast cell-mediated allergic reactions. In this review, we discuss potential physiological roles of this RGS protein subfamily, primarily in leukocytes having central roles in immune and inflammatory responses. We also discuss approaches to target RGS proteins therapeutically, which represents a virtually untapped strategy to combat exaggerated immune responses leading to inflammation.
Topics: Animals; Humans; Immunity, Cellular; Inflammation; Inflammation Mediators; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 26597290
DOI: 10.1208/s12248-015-9847-0 -
Cellular Signalling Jan 2018Regulators of G protein signaling (RGS) are a family of proteins classically known to accelerate the intrinsic GTPase activity of G proteins, which results in... (Review)
Review
Regulators of G protein signaling (RGS) are a family of proteins classically known to accelerate the intrinsic GTPase activity of G proteins, which results in accelerated inactivation of heterotrimeric G proteins and inhibition of G protein coupled receptor signaling. RGS proteins play major roles in essential cellular processes, and dysregulation of RGS protein expression is implicated in multiple diseases, including cancer, cardiovascular and neurodegenerative diseases. The expression of RGS proteins is highly dynamic and is regulated by epigenetic, transcriptional and post-translational mechanisms. This review summarizes studies that report dysregulation of RGS protein expression in disease states, and presents examples of drugs that regulate RGS protein expression. Additionally, this review discusses, in detail, the transcriptional and post-transcriptional mechanisms regulating RGS protein expression, and further assesses the therapeutic potential of targeting these mechanisms. Understanding the molecular mechanisms controlling the expression of RGS proteins is essential for the development of therapeutics that indirectly modulate G protein signaling by regulating expression of RGS proteins.
Topics: Animals; Azacitidine; Benzodiazepines; Cardiovascular Diseases; Drugs, Investigational; Epigenesis, Genetic; GTP-Binding Proteins; Humans; Hydroxamic Acids; Neoplasms; Neurodegenerative Diseases; Olanzapine; Protein Processing, Post-Translational; RGS Proteins; Signal Transduction; Vorinostat
PubMed: 29042285
DOI: 10.1016/j.cellsig.2017.10.007 -
The Journal of Biological Chemistry Dec 2019G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly,... (Review)
Review
G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.
Topics: Animals; GTP-Binding Proteins; Humans; Protein Structure, Secondary; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31636120
DOI: 10.1074/jbc.REV119.007060 -
Frontiers in Endocrinology 2022Regulator of G protein signaling (RGS) proteins are critical negative molecules of G protein-coupled receptor (GPCR) signaling, which mediates a variety of biological... (Review)
Review
Regulator of G protein signaling (RGS) proteins are critical negative molecules of G protein-coupled receptor (GPCR) signaling, which mediates a variety of biological processes in bone homeostasis and diseases. The RGS proteins are divided into nine subfamilies with a conserved RGS domain which plays an important role in regulating the GTPase activity. Mutations of some RGS proteins change bone development and/or metabolism, causing osteopathy. In this review, we summarize the recent findings of RGS proteins in regulating osteoblasts, chondrocytes, and osteoclasts. We also highlight the impacts of RGS on bone development, bone remodeling, and bone-related diseases. Those studies demonstrate that RGS proteins might be potential drug targets for bone diseases.
Topics: Bone Diseases; Bone and Bones; GTP-Binding Proteins; Humans; RGS Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 35573989
DOI: 10.3389/fendo.2022.842421 -
BioEssays : News and Reviews in... Apr 2016Regulators of G protein signaling (RGS) proteins provide timely termination of G protein-coupled receptor (GPCR) responses. Serving as a central control point in GPCR... (Review)
Review
Regulators of G protein signaling (RGS) proteins provide timely termination of G protein-coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti-inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS proteins. We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide.
Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Gastrointestinal Motility; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases; Intestines; Mice; RGS Proteins; Receptors, Cannabinoid; Receptors, Opioid; Receptors, Serotonin; Signal Transduction; Small Molecule Libraries; Visceral Pain
PubMed: 26817719
DOI: 10.1002/bies.201500118 -
Frontiers in Immunology 2022Alterations in lipid metabolism promote tumor progression. However, the role of lipid metabolism in the occurrence and development of gastric cancer have not been fully...
BACKGROUND
Alterations in lipid metabolism promote tumor progression. However, the role of lipid metabolism in the occurrence and development of gastric cancer have not been fully clarified.
METHOD
Here, genes that are related to fatty acid metabolism and differentially-expressed between normal and gastric cancer tissues were identified in the TCGA-STAD cohort. The intersection of identified differentially-expressed genes with Geneset was determined to obtain 78 fatty acid metabolism-related genes. The ConsensusClusterPlus R package was used to perform differentially-expressed genes, which yielded divided two gastric cancer subtypes termed cluster 1 and cluster 2.
RESULTS
Patients in cluster 2 was found to display poorer prognosis than patients in cluster 1. Using machine learning method to select 8 differentially expressed genes among subtypes to construct fatty acid prognostic risk score model (FARS), which was found to display good prognostic efficacy. We also identified that certain anticancer drugs, such as bortezomib, elesclomol, GW843682X, and nilotinib, showed significant sensitivity in the high FARS score group. RGS2 was selected as the core gene upon an analysis of the gastric cancer single-cell, and Western blotting and immunofluorescence staining results revealed high level of expression of this gene in gastric cancer cells. The results of immunohistochemical staining showed that a large amount of RGS2 was deposited in the stroma in gastric cancer. A pan-cancer analysis also revealed a significant association of RGS2 with TMB, TIDE, and CD8+ T-cell infiltration in other cancer types as well. RGS2 may thus be studied further as a new target for immunotherapy in future studies on gastric cancer.
CONCLUSION
In summary, the FARS model developed here enhances our understanding of lipid metabolism in the TME in gastric cancer, and provides a theoretical basis for predicting tumor prognosis and clinical treatment.
Topics: Humans; Biomarkers, Tumor; Blotting, Western; Fatty Acids; RGS Proteins; Stomach Neoplasms; Tumor Microenvironment; Antineoplastic Agents; Prognosis; Machine Learning
PubMed: 36591293
DOI: 10.3389/fimmu.2022.1065927 -
Therapeutic Advances in Cardiovascular... 2023G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be... (Review)
Review
G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type, and this applies to the myocardium as well. A large number of studies have provided substantial evidence for the roles various RGS proteins expressed in cardiomyocytes play in cardiac physiology and heart disease pathophysiology. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of specific heart diseases, such as heart failure and atrial fibrillation. We focus on cardiac RGS4 in particular, since this isoform appears to be selectively (among the RGS protein family) upregulated in human heart failure and is also the target of ongoing drug discovery efforts for the treatment of a variety of diseases.
Topics: Animals; Humans; RGS Proteins; Signal Transduction; Heart; GTP-Binding Proteins; Heart Diseases; Heart Failure; Mammals
PubMed: 37724539
DOI: 10.1177/17539447231199350