The Arabidopsis thaliana heterotrimeric G protein complex is encoded by single canonical Galpha and Gbeta subunit genes and two Ggamma subunit genes (AGG1 and AGG2), raising the possibility that the two potential G protein complexes mediate different cellular processes. Mutants with reduced expression of one or both Ggamma genes revealed specialized roles for each Ggamma subunit. AGG1-deficient mutants, but not AGG2-deficient mutants, showed impaired resistance against necrotrophic pathogens, reduced induction of the plant defensin gene PDF1.2, and decreased sensitivity to methyl jasmonate. By contrast, both AGG1- and AGG2-deficient mutants were hypersensitive to auxin-mediated induction of lateral roots, suggesting that Gbetagamma1 and Gbetagamma2 synergistically inhibit auxin-dependent lateral root initiation. However, the involvement of each Ggamma subunit in this root response differs, with Gbetagamma1 acting within the central cylinder, attenuating acropetally transported auxin signaling, ...
The phosphorylation of heptahelical receptors by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor kinases (GRKs) is a universal regulatory mechanism that leads to desensitization of G protein signaling and to the activation of alternative signaling pathways.We determined the crystallographic structure of bovine GRK2 in complex with G protein beta1gamma2 subunits.Our results show how the three domains of GRK2-the RGS (regulator of G protein signaling) homology, protein kinase, and pleckstrin homology domains-integrate their respective activities and recruit the enzyme to the cell membrane in an orientation that not only facilitates receptor phosphorylation, but also allows for the simultaneous inhibition of signaling by Galpha and Gbetagamma subunits ...
Resistance to inhibitors of cholinesterase (Ric-8) proteins are ∼60-kDa positive regulators of heterotrimeric G protein α subunits found in animals and some fungi. Ric-8 was discovered in the Caenorhabditis elegans ric genetic screen that was conducted to find mutants with reduced neurotransmitter release. ric mutants live by circumventing the neurotoxic effects of cholinesterase inhibitor-induced synaptic acetylcholine accumulation (Miller et al., 1996). Wild-type RIC genes positively influence neurotransmission and include components of G protein signaling pathways: Gαq/egl-30, RGS/egl-10, and unc-13, which encodes a protein that regulates synaptic vesicle priming in response to diacylglycerol. RIC-8 encoded an uncharacterized protein also called synembryn in some databases. ric-8 mutants were epistatic to egl-30 (Gαq) mutants, indicating that RIC-8 protein action was likely manifested upstream of Gαq or in a parallel pathway (Miller et al., 2000). ric-8 mutants were later found to be ...
Gene Information Heterotrimeric guanine nucleotide-binding proteins (G proteins) which integrate signals between receptors and effector proteins are composed of an alpha a beta and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits as well as of certain signal transduction receptors and effectors. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq Jul 2008]. ...
Information transfer from activated heterotrimeric guanine nucleotide-binding proteins (G proteins) to downstream effectors occurs through noncovalent protein-protein interactions. Such interactions involve multiple regions of contact between the G protein and the effector. Some of these regions mediate information transfer, as defined by their ability to change the activity of their downstream binding partners, whereas other interactions appear to contribute solely to binding affinity. Such modular configurations occur in functionally diverse proteins such as myosin and a regulator of the double-stranded DNA stimulated protein kinase (PKR) called PACT. In most cases, it appears that both charge complementarity and the architecture of the interacting surfaces provide the appropriate balance between specificity of interactions and their reversibility. Information transfer regions appear to display conformational flexibility in interactions. Such flexible interactions may be essential for the ...
Ric-8A and Ric-8B are positive regulators of heterotrimeric G protein a subunit function. We have recently defined the cellular action of Ric-8 proteins towards...
Members of the G protein-coupled receptor (GPCR) family, such as GPR85, have a similar structure characterized by 7 transmembrane domains. Activation of GPCRs by extracellular stimuli, such as neurotransmitters, hormones, or light, induces an intracellular signaling cascade mediated by heterotrimeric GTP-binding proteins, or G proteins (Matsumoto et al., 2000 [PubMed 10833454]).[supplied by OMIM, Aug 2008 ...
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Gα subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Gα when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Gα, RGS domain binding consequently accelerates Gα-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Gα substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their ...
We identified the transcription factor E2F8 in the course of a screen for novel activators of heterotrimeric G proteins. In S. cerevisiae, E2F8 was able to activate a G protein/MAP kinase reporter pathway; this activity was specific for particular G protein isoforms, mapped epistatically to the level of heterotrimers, and was antagonized by a GTPase-accelerating protein. The amino-terminus of the protein appeared to be most important for G protein activation. The most parsimonious interpretation of these results is that E2F8 stimulates nucleotide exchange on the α subunit of heterotrimeric G proteins. Since E2F8 did not reduce the maximal receptor-mediated signal (Figure 2), but rather caused a left-shift in the receptors dose-response curve, E2F8 does not compete with receptors for G proteins. Instead, E2F8 and receptors may be complementary to one another in their mode of action, using different molecular mechanisms to activate Gα.. G protein activation would be a novel function for an E2F ...
Cells usually activate the cyclic AMP (cAMP, or adenosine 3′,5′-monophosphate)-dependent protein kinase through G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, which activate G proteins, which in turn control the activity of adenylyl cyclase, the enzyme that makes cAMP. Peeters et al., however, report that in yeast, and just maybe in mammalian cells as well, there appears to be a more direct route to activation of the cAMP-dependent protein kinase (PKA). Peeters et al. studied the roles of Krh1 (kelch-repeat homologue 1, also called Gpb2) and Krh2 (also called Gpb1). Krh1 and Krh2 associate with the yeast G protein α subunit Gpa2, which appears not to interact with canonical G protein β-γ subunits. Interestingly, the Krh1 and Krh2 proteins have the seven-bladed β-propeller structure characteristic of Gβ proteins. Deletion of Krh1 and Krh2 resulted in a phenotype indicative of high PKA activity, but there was no associated increase in the abundance of ...
Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. ...
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 is a protein that in humans is encoded by the GNB3 gene. Heterotrimeric guanine nucleotide-binding proteins ( G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Additional splice variants may exist for this gene, but they have not been fully described. GRCh38: Ensembl release 89: ...
Introduction. G protein-coupled receptors (GPCRs) form the largest family of integral membrane receptors. These receptors are seven transmembrane-spanning proteins that respond to a wide variety of stimuli including light, odour, taste, hormones and neurotransmitters. Activation of a GPCR results in the modulation of intracellular second messenger levels and/or ionic conductances via the coupling of receptors to a wide variety of effector systems via heterotrimeric guanine nucleotide-binding proteins (G proteins). Agonist activation of a GPCR induces the isomerization of the receptor to a high-affinity agonist-binding conformation catalyzing the exchange of GDP for GTP on the G protein a-subunit (1). This exchange of GDP for GTP allows the dissociation of the Ga-subunit from the Gßg-subunits, which when dissociated from one another regulate the activity of effector systems such as adenylyl cyclase and potassium channels.. Shortly following exposure to an agonist, GPCR responsiveness wanes as ...
heterotrimeric G-protein complex, G protein-coupled receptor binding, G-protein beta/gamma-subunit complex binding, GTPase activity, adenylate cyclase-modulating G protein-coupled receptor signaling pathway, phospholipase C-activating dopamine receptor signaling pathway
Heterotrimeric guanine nucleotide binding proteins (G proteins) transmit a variety of extracellular signals from cell surface G protein-coupled receptors (GPCRs) to intracellular effector molecules. Heterotrimeric G proteins are classified according to the α subunit into four subfamilies: Gs, Gi, Gq, and G12. The G12 subfamily, which is comprised of two members, Gα12 (GNA12) and Gα13 (GNA13), has been implicated in cancer cell invasion and metastasis. G12 signaling promotes prostate, breast and ovarian cancer cell invasion in vitro, and these proteins are highly expressed in metastatic cancer tissues. As part of a program to elucidate the mechanisms by which GNA12 and GNA13 expression is upregulated in cancer cells, we assessed the potential involvement of micro-RNAs (miRNAs) in post-transcriptional control of GNA13 expression. The initial focus was on prostate cancer; LnCAP (with the lowest GNA13 protein level) and PC3 (with the highest GNA13 level) were employed as the model system. ...
Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulate signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. Alternatively spliced transcript variants have been found for this gene ...
One of the best understood signal transduction pathways activated by receptors containing seven transmembrane domains involves activation of heterotrimeric G-protein complexes containing Gs, the subsequent stimulation of adenylyl cyclase, production of cAMP, activation of protein kinase A (PKA), and the phosphorylation of substrates that control a wide variety of cellular responses. Here, we report the identification of "loss-of-function" mutations in the Drosophila Gs gene (dgs). Seven mutants have been identified that are either complemented by transgenes representing the wild-type dgs gene or contain nucleotide sequence changes resulting in the production of altered Gsprotein. Examination of mutant alleles representing loss-of-Gs function indicates that the phenotypes generated do not mimic those created by mutational elimination of PKA. These results are consistent with the conclusion reached in previous studies that activation of PKA, at least in these developmental contexts, does not ...
Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Galpha. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Galpha-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Galpha caused by binding of GBA proteins with residue-level resolution. We find that the GBA motif binds to the SwitchII/alpha3 cleft of Galpha and induces changes in the G-1/P-loop and G-2 boxes (involved in phosphate binding), but not in the G-4/G-5 boxes (guanine binding). Our findings reveal that G-protein-binding and activation mechanisms are fundamentally different between GBA proteins and GPCRs, and that GEF-mediated ...
Combining with an extracellular amine and transmitting the signal across the membrane by activating an associated G-protein; promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex.
The presence of a complete repertoire of heterotrimeric G-protein complex components and its regulator in a green alga confirms that the origin of this signaling mechanism in plants is more ancient than previously thought and is not related to the colonization of land by plants. ...
The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanosine nucleotide-binding proteins, consist of three subunits, called alpha, beta, and gamma subunits, or Gα, Gβ, and Gγ. When a G protein-coupled receptor (GPCR) is activated, Gα dissociates from Gβγ, allowing both subunits to perform their respective downstream signaling effects. One of the major functions of Gβγ is the inhibition of the Gα subunit. The individual subunits of the G protein complex were first identified in 1980 when the regulatory component of adenylate cyclase was successfully purified, yielding three polypeptides of different molecular weights. Initially, it was thought that Gα, the largest subunit, was the major effector regulatory subunit, and that Gβγ was largely responsible for inactivating the Gα subunit and enhancing membrane binding. However, ...
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
Our laboratory studies signal transduction systems controlled by heterotrimeric G proteins as well as Ras-related GTPases. The superfamily of GTPases control numerous signaling cascades based upon the regulated binding, hydrolysis, and exchange of guanine nucleotides; GTPases bound to GTP are active in downstream signaling while those bound to GDP are inactive. Mutant GTPases with abnormal GDP/GTP cycling are implicated in numerous human diseases, including cancer. It is our desire to better understand the regulation of heterotrimeric G proteins and Ras-related GTPases at the molecular level with the ultimate goal of using this information to design therapies to correct abnormal signaling mediated by these proteins and thereby treat associated pathologies.. ...
This gene encodes a member of the sorting nexin family. Members of this family have a phox (PX) phosphoinositide binding domain and are involved in intracellular trafficking. The encoded protein also contains a regulator of G protein signaling (RGS) domain. Regulator of G protein signaling family members are regulatory molecules that act as GTPase activating proteins for G alpha subunits of heterotrimeric G proteins. Alternate splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014] ...
GNG12 Human Recombinant produced in E.Coli is a single, non-glycosylated polypeptide chain containing 92 aa (1-69 a.a) and having a molecular mass of 10.1kDa.
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Complete information for GNB3 gene (Protein Coding), G Protein Subunit Beta 3, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Regulation of low-voltage activated T-type Ca2+ channel activity by kinases and heterotrimeric G-proteins and their roles in physiological responses.. ...
GNB2兔单克隆抗体[EPR3261Y](ab81272)可与小鼠, 大鼠, 人样本反应并经WB, IP, IHC, ICC, Flow Cyt实验严格验证并得到1个独立的用户反馈。所有产品均提供质保服务,中国75%以上现货。
Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family. We demonstrated that a constitutively monomeric CXCL12 variant reproduced the G protein-dependent and β-arrestin-dependent responses that are associated with normal CXCR4 signaling and lead to cell migration. In addition, monomeric CXCL12 made specific contacts with CXCR4 that are not present in the structure of the receptor in complex with a dimeric form of CXCL12, a biased agonist that stimulates only G protein-dependent signaling. We produced an ...
G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein α subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism. ...
Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as ...
Summary is not available for the mouse gene. This summary is for the human ortholog.] Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulate signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008 ...
Diversity of G-Protein-Coupled Receptor Signal Transduction Pathways
Receptors coupled to heterotrimeric GTP-binding proteins (G-proteins) are integral transmembrane proteins that transduce extracellular signals to the cell interior. G-protein-coupled receptors exhibit a common structural motif consisting of seven membrane spanning regions. Receptor occupation promotes interaction between the receptor and the G-protein on the interior surface of the membrane. This induces an exchange of GDP for GTP on the G-protein α subunit and dissociation of the α subunit from the β γ heterodimer. Depending on its isoform, the GTP α subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylate cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channel or kinase function.
References:
Schoneberg, T., et al., Structural basis of G-protein-coupled receptor function. Mol. Cell. Endocrinol. 151, 181-193 (1999).
Press Release issued Sep 14, 2012: G protein coupled receptors which are also known by other names such as heptahelical receptors, G protein-linked receptors (GPLR), serpentine receptor and 7TM receptors comprises of a large family of protein. They are found in eukaryotes and choanoflagellates. GPCRs are targeted by approximately 45% to 50% of medicinal drugs.The major factors which are driving the growth of the GPCRs market include: growing researcher interest in targeting GPCR for medicinal drugs, development in indentifying new membrane structure and newer structures and the advancement in technologies used.
The G-protein-coupled receptors (GPCRs, also called seven-transmembrane receptor, 7TMRs, or heptahelical receptor) are a conserved family of seven transmembrane receptors which are essential not only in the healthy heart and blood vessels but also in for treatment and therapy of cardiovascular disease and failure. Heart failure is a global leading cause of morbidity and death and as such understanding 7TMRs, their functions, structures and potential for therapy is essential. This review will investigate the roles of the receptors in the healthy functioning cardiovascular system, and in cardiac disorders with an emphasis in cardiomyopathy. It will also explore the role of autoimmunity and autoantibodies against the G-protein-coupled receptors in cardiomyopathy.. ...
TY - JOUR. T1 - The active role of βγ in signal transduction. AU - Sternweis, Paul C.. PY - 1994. Y1 - 1994. N2 - Many receptors that sense the environment effect intracellular regulation through stimulation of heterotrimeric G proteins and the consequences thereof. While prominence was originally given to the α-subunits of G proteins as the pathway for downstream regulation, very active roles for the βγ-subunits have emerged in the past year. Recent experiments highlight the versatility of βγ-subunits in these regulatory pathways, but also emphasize some fundamental questions that remain.. AB - Many receptors that sense the environment effect intracellular regulation through stimulation of heterotrimeric G proteins and the consequences thereof. While prominence was originally given to the α-subunits of G proteins as the pathway for downstream regulation, very active roles for the βγ-subunits have emerged in the past year. Recent experiments highlight the versatility of βγ-subunits ...
Upon ligand binding, G-protein-coupled receptors (GPCRs) impart the transmission to heterotrimeric G proteins composed of , , and subunits, leading to dissociation of the G subunit from your G subunit. and its deletion mutants were cloned into pEGFP-C1 (Clontech, Mountain View, CA) to fuse with an enhanced green fluorescence protein (EGFP) at the N terminus (21). The GFP-tagged bovine GRK2 was kindly provided by Marc G. Caron (Duke School INFIRMARY, Durham, NC). The Flag-tagged GRK2ct that spans proteins (aa) 501 to 689 on the C-terminal part of GRK2 was subcloned from GFP-tagged GRK2. The RKTG brief hairpin RNA (shRNA) build was generated utilizing a lentiviral program as previously reported (27). In a nutshell, an annealed little interfering RNA (siRNA) cassette using a concentrating on series of GGACAACCCGUACAUCACC for RKTG was placed in to the pBS-SKII-hU6 vector downstream from the hU6 promoter. The siRNA expression cassette was subcloned in to the FG12 vector and confirmed by DNA ...
G protein alpha S兔多克隆抗体(ab97629)可与人样本反应并经WB实验严格验证。中国75%以上现货,所有产品均提供质保服务,可通过电话、电邮或微信获得本地专属技术支持。
Complete information for GNAT2 gene (Protein Coding), G Protein Subunit Alpha Transducin 2, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric guanine nucleotide-binding protein (G protein) Gαq and thereby links Gαq-coupled receptors (GPCRs) to the activation of the small-molecular-weight G protein RhoA. We determined the crystal structure of the Gαq-p63RhoGEF-RhoA complex, detailing the interactions of Gαq with the Dbl and pleckstrin homology (DH and P ...
The lipoglycoproteins of the WNT family act on seven transmembrane-spanning Class Frizzled receptors. Here, we show that WNT-5A evokes a proliferative response in a mouse microglia-like cell line (N13), which is sensitive to pertussis toxin, thus implicating the involvement of heterotrimeric G proteins of the G(i/o) family. We continue to show that WNT-5A stimulation of N13 membranes and permeabilized cells evokes the exchange of GDP for GTP of pertussis toxin-sensitive G proteins employing [gamma-(35)S]GTP assay and activity state-specific antibodies to GTP-bound G(i) proteins. Our functional analysis of the PTX-sensitivity of WNT-induced G protein activation and PCR analysis of G protein and FZD expression patterns suggest that WNT-5A stimulation leads to the activation of G(i2/3) proteins in N13 cells possibly mediated by FZD(5), the predominant FZD expressed ...
TY - JOUR. T1 - Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi. AU - Qi, Xiaofeng. AU - Liu, Heng. AU - Thompson, Bonne. AU - McDonald, Jeffrey. AU - Zhang, Cheng. AU - Li, Xiaochun. PY - 2019/1/1. Y1 - 2019/1/1. N2 - The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway1,2. It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins3. Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO ...
By using MT1 homodimers and MT1/MT2 heterodimers as model GPCRs, we are extending here two emerging concepts: the pre‐assembly of GPCR‐interacting complexes and the asymmetric function and organization of GPCR dimers. In addition, we are providing a new functional justification for GPCR dimerization that applies to homo‐ and heterodimers, namely the possibility of simultaneous and direct binding of GPCR‐interacting proteins (GIPs) to the same GPCR dimer composed of two asymmetric protomers. Heterotrimeric G proteins are central, although not exclusive signal transducers of GPCRs. An increasing number of reports suggests the formation of pre‐assembled receptor-G‐protein complexes, which rearrange upon agonist activation of the receptor (Bunemann et al, 2003; Galés et al, 2006; Audet et al, 2008). This central complex is surrounded by a number of other GIPs that might either compete with the G protein for receptor binding, as in the case of arrestin (Lohse et al, 1990), or ...
Exposure to external stimuli promotes a variety of cellular responses including changes in morphology, gene expression and cell division status. These responses are promoted by signaling pathways composed of modules that are conserved from lower to higher eukaryotes. In Saccharomyces cerevisiae response to the external stimuli provided by mating pheromone is governed by the pheromone response pathway. This pathway is composed of a G protein coupled receptor/heterotrimeric G protein (Gαβγ) module and a MAP kinase cascade. Activation of this pathway allows the heterotrimeric G protein βγ dimer (Gβγ) to recruit polarity proteins to promote changes in cell morphology and to activate signaling through the MAP kinase cascade. Here we investigate the regulation of these pheromone-induced responses. We first examine how an asymmetric polarization response is generated. Normally, a gradient of pheromone serves as a spatial cue for formation of a polarized mating projection, but cells can still polarize
Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The Interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y2502.39) in the intracellular loop 1 (ILl) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, impaired in DVL2 binding, was defective in both beta-catenin-dependent and beta-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gan and G alpha13 and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics ...
Cytoskeletal signaling complexes include G-protein complexes, focal adhesions, and adherens junctions. Focal adhesions and adherens junctions link the cell exterior to the plasma membrane and the actin cytoskeleton, acting as key initiators of signaling pathways in response to cell adhesion.
Heart failure (HF) has been described as the inability of the myocardium to deliver oxygen and nutrients to a degree commensurate with the metabolic requirements of the body.1 Myocardial dysfunction induces compensatory neurohumoral mechanisms, including the sympathetic nervous system (SNS), as an attempt to preserve contractile performance. Mediators of the SNS consist predominantly of 2 catecholamines, namely epinephrine and norepinephrine (NE), released by cardiac sympathetic nerve terminals or secreted directly into the circulation by the adrenal medulla. Effects of these neurotransmitters are mediated through cell surface adrenergic receptors (ARs), members of the G protein-coupled receptor superfamily. Stimulation of the β-AR promotes a conformational change to activate the heterotrimeric G protein Gα and Gβγ subunits, promoting positive inotropic and chronotropic effects culminating in improved myocardial function.2. Article, see p 1116. This functionally beneficial pathway refers ...
The Gs alpha subunit (Gαs, Gsα, or Gs protein) is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylyl cyclase. It is one of the three main families of G proteins: Gαi/Gαo, Gαq, and Gαs.[1] A mnemonic for remembering this subunit is to look at the first letter (Gαs = Adenylate Cyclase stimulator). ...
Mutually exclusive mutations affecting exon 4, codon 183 or exon 5, codon 209, of the G protein α-subunit Q (GNAQ) gene and the G protein α-subunit 11 (GNA11) gene are found in approx 84% of uveal melanomas. The identification of the mutational profile of exons 4 and 5 of GNAQ/GNA11 will facilitate improvement in our knowledge of these neoplasms, and may be useful for selection of patients for targeted therapeutic approaches. ...