scholarly journals Multi-omics analysis of multiple glucose-sensing receptor systems in yeast

2021 ◽  
Author(s):  
Shuang Li ◽  
Yuanyuan Li ◽  
Blake R. Rushing ◽  
Sarah E. Harris ◽  
Susan L. McRitchie ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
Glucose Sensing ◽  
Glucose Detection ◽  
Yeast Saccharomyces Cerevisiae ◽  
Glucose Signaling ◽  
Cognate Receptor ◽  
Small G Protein ◽  
Dependent Signal ◽  
G Protein Coupled

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) and two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G protein transmits the signal from its cognate receptor, while the small G protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast.

scholarly journals The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors

2018 ◽  
Vol 14 (3) ◽  
pp. 284-290 ◽  
Author(s):  
Lisa Joedicke ◽  
Jiafei Mao ◽  
Georg Kuenze ◽  
Christoph Reinhart ◽  
Tejaswi Kalavacherla ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
G Protein Coupled Receptors ◽  
Subtype Selectivity ◽  
G Protein Coupled

scholarly journals Structure of the Mouse Sex Peptide Pheromone ESP1 Reveals a Molecular Basis for Specific Binding to the Class C G-protein-coupled Vomeronasal Receptor

2013 ◽  
Vol 288 (22) ◽  
pp. 16064-16072 ◽  
Author(s):  
Sosuke Yoshinaga ◽  
Toru Sato ◽  
Makoto Hirakane ◽  
Kaori Esaki ◽  
Takashi Hamaguchi ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
Specific Binding ◽  
Sex Peptide ◽  
Vomeronasal Receptor ◽  
Peptide Pheromone ◽  
Class C ◽  
G Protein Coupled

scholarly journals Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 with Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 1007-1013 ◽  
Author(s):  
Tony M. Plant ◽  
Suresh Ramaswamy ◽  
Meloni J. DiPietro
Keyword(s):  
G Protein ◽  
Concomitant Treatment ◽  
Secondary Effects ◽  
G Protein Coupled Receptor ◽  
Gnrh Release ◽  
Dependent Signal ◽  
Lh Release ◽  
Lh Secretion ◽  
G Protein Coupled

The purpose of the present study was to further examine the hypothesis that activation of G protein-coupled receptor 54 (GPR54) signaling at the end of the juvenile phase of primate development is responsible for initiation of gonadarche and the onset of puberty. Accordingly, we determined whether repetitive iv administration of the GPR54 receptor agonist kisspeptin-10 (2 μg as a brief 1-min infusion once every hour for 48 h) to the juvenile male rhesus monkey would prematurely elicit sustained, pulsatile release of hypothalamic GnRH, the neuroendocrine trigger for gonadarche. GnRH release was monitored indirectly by measuring LH secretion from the in situ pituitary, the GnRH responsiveness of which had been heightened before the experiment with an intermittent iv infusion of synthetic GnRH. Agonadal animals (n = 4) were employed to eliminate any confounding and secondary effects of changing feedback signals from the testis. The first brief infusion of kisspeptin-10 evoked an LH discharge that mimicked those produced by GnRH priming, and this was followed by a train of similar LH discharges in response to hourly activation of GPR54 by repetitive kisspeptin-10 administration. Concomitant treatment with a GnRH receptor antagonist, acyline, abolished kisspeptin-10-induced LH release. Repetitive kisspeptin-10 administration also provided a GnRH-dependent signal to FSH secretion. These findings are consistent with the notion that, in primates, the transition from the juvenile (attenuated GnRH release) to pubertal (robust GnRH release) state is controlled by activation of GPR54 resulting from increased expression of hypothalamic KiSS-1 and release of kisspeptin in this region of the brain.

scholarly journals Pro-Aging Effects of Glucose Signaling through a G Protein-Coupled Glucose Receptor in Fission Yeast

PLoS Genetics ◽  
2009 ◽  
Vol 5 (3) ◽  
pp. e1000408 ◽  
Author(s):  
Antoine E. Roux ◽  
Alexandre Leroux ◽  
Manal A. Alaamery ◽  
Charles S. Hoffman ◽  
Pascal Chartrand ◽  
...  
Keyword(s):  
Fission Yeast ◽  
G Protein ◽  
Aging Effects ◽  
Glucose Signaling ◽  
G Protein Coupled

Molecular basis of G protein-coupled receptor high affinity for gastrin-releasing peptide (GRP)

2003 ◽  
Vol 124 (4) ◽  
pp. A469
Author(s):  
Tomoo Nakagawa ◽  
Jose A. Tapia ◽  
Kenji Tokita ◽  
Samuel Mantey ◽  
Michael Schumann ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
G Protein Coupled Receptor ◽  
Gastrin Releasing Peptide ◽  
High Affinity ◽  
G Protein Coupled

scholarly journals Molecular Basis of Secretin Docking to Its Intact Receptor Using Multiple Photolabile Probes Distributed throughout the Pharmacophore

2011 ◽  
Vol 286 (27) ◽  
pp. 23888-23899 ◽  
Author(s):  
Maoqing Dong ◽  
Polo C.-H. Lam ◽  
Delia I. Pinon ◽  
Keiko Hosohata ◽  
Andrew Orry ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
Peptide Mapping ◽  
G Protein Coupled Receptors ◽  
Peptide Ligands ◽  
Amino Terminus ◽  
Amino Terminal ◽  
Binding Cleft ◽  
Mutant Receptors ◽  
G Protein Coupled

The molecular basis of ligand binding and activation of family B G protein-coupled receptors is not yet clear due to the lack of insight into the structure of intact receptors. Although NMR and crystal structures of amino-terminal domains of several family members support consistency in general structural motifs that include a peptide-binding cleft, there are variations in the details of docking of the carboxyl terminus of peptide ligands within this cleft, and there is no information about siting of the amino terminus of these peptides. There are also no empirical data to orient the receptor amino terminus relative to the core helical bundle domain. Here, we prepared a series of five new probes, incorporating photolabile moieties into positions 2, 15, 20, 24, and 25 of full agonist secretin analogues. Each bound specifically to the receptor and covalently labeled single distinct receptor residues. Peptide mapping of labeled wild-type and mutant receptors identified that the position 15, 20, and 25 probes labeled residues within the distal amino terminus of the receptor, whereas the position 24 probe labeled the amino terminus adjacent to TM1. Of note, the position 2 probe labeled a residue within the first extracellular loop of the receptor, a region not previously labeled, providing an important new constraint for docking the amino-terminal region of secretin to its receptor core. These additional experimentally derived constraints help to refine our understanding of the structure of the secretin-intact receptor complex and provide new insights into understanding the molecular mechanism for activation of family B G protein-coupled receptors.

scholarly journals Molecular basis for the evolved instability of a human G-protein coupled receptor

Cell Reports ◽  
2021 ◽  
Vol 37 (8) ◽  
pp. 110046
Author(s):  
Laura M. Chamness ◽  
Nathan B. Zelt ◽  
Haley R. Harrington ◽  
Charles P. Kuntz ◽  
Brian J. Bender ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Molecular Basis for G-protein-Coupled Receptor (GPCR) Activation and Biased Signalling at the Platelet Thrombin Receptor Proteinase Activated Receptor-4 (PAR4)

2019 ◽  
Author(s):  
Pierre E. Thibeault ◽  
Jordan C. LeSarge ◽  
D’Arcy Arends ◽  
Michaela Fernandes ◽  
Peter Chidiac ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Molecular Basis ◽  
Calcium Signalling ◽  
Cathepsin G ◽  
Mitogen Activated Protein Kinase ◽  
Proteolytic Activation ◽  
Gpcr Activation ◽  
Tethered Ligand ◽  
G Protein Coupled

AbstractProteinase Activated Receptor-4 (PAR4) is a member of the proteolytically-activated PAR family of G-Protein-coupled Receptors (GPCRs). PARs are activated following proteolytic cleavage of the receptor N-terminus by enzymes such as thrombin, trypsin, and cathepsin-G to reveal the receptor-activating motif termed the tethered ligand. The tethered ligand binds intramolecularly to the receptor and triggers receptor signalling and cellular responses. In spite of this unusual mechanism of activation, PARs are fundamentally peptide receptors and can also be activated by exogenous application of short synthetic peptides derived from the tethered ligand sequence. In order to gain a better understanding of the molecular basis for PAR4-dependent signalling, we examined signalling responses to a library of peptides derived from the canonical PAR4 activating peptide (PAR4-AP), AYPGKF-NH2. We examined peptide residues involved in activation of the Gαq/11-coupled calcium signalling pathway, β-arrestin recruitment, and mitogen-activated protein kinase pathway activation. The peptide N-methyl-alanine-YPGKF-NH2 was identified as a compound that is a poor activator of PAR4-dependent calcium signalling but was fully competent in recruiting β-arrestin-1 and -2. In order to gain a better understanding of the ligand-binding pocket, we used in silico docking to identify key residues involved in PAR4 interaction with AYPGKF-NH2. The predicted interactions were verified by site-directed mutagenesis and analysis of calcium signalling and β-arrestin-1/-2 recruitment following proteolytic activation (with thrombin) or activation with the synthetic agonist peptide (AYPGKF-NH2). We determined that a key extracellular loop-2 aspartic acid residue (Asp230) is critical for signalling following both proteolytic and peptide activation of PAR4. Finally, we investigated platelet aggregation in response to AyPGKF-NH2 (a peptide with D-tyrosine in position two) which is unable to activate calcium signalling, and AYPGRF-NH2 a peptide that is equipotent to the parental peptide AYPGKF-NH2 for calcium signalling but is more potent at recruiting β-arrestins. We found that AyPGKF-NH2 fails to activate platelets while AYPGRF-NH2 causes a platelet aggregation response that is greater than that seen with the parental peptide and is comparable to that seen with thrombin stimulation. Overall, these studies uncover molecular determinants for agonist binding and signalling through a non-canonically activated GPCR and provide a template for development of small molecule modulators of PAR4.

scholarly journals Multi-omics analysis of glucose-mediated signaling by a moonlighting Gβ protein Asc1/RACK1

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009640
Author(s):  
Shuang Li ◽  
Yuanyuan Li ◽  
Blake R. Rushing ◽  
Sarah E. Harris ◽  
Susan L. McRitchie ◽  
...  
Keyword(s):  
G Protein ◽  
Glucose Sensing ◽  
Heterotrimeric G Proteins ◽  
Glucose Addition ◽  
Protein Subunits ◽  
Individual Gene ◽  
Gene Transcripts ◽  
G Protein Coupled

Heterotrimeric G proteins were originally discovered through efforts to understand the effects of hormones, such as glucagon and epinephrine, on glucose metabolism. On the other hand, many cellular metabolites, including glucose, serve as ligands for G protein-coupled receptors. Here we investigate the consequences of glucose-mediated receptor signaling, and in particular the role of a Gα subunit Gpa2 and a non-canonical Gβ subunit, known as Asc1 in yeast and RACK1 in animals. Asc1/RACK1 is of particular interest because it has multiple, seemingly unrelated, functions in the cell. The existence of such “moonlighting” operations has complicated the determination of phenotype from genotype. Through a comparative analysis of individual gene deletion mutants, and by integrating transcriptomics and metabolomics measurements, we have determined the relative contributions of the Gα and Gβ protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Of the two subunits, Gpa2 regulates a greater number of gene transcripts and was particularly important in determining the amplitude of response to glucose addition. We conclude that the two G protein subunits regulate distinct but complementary processes downstream of the glucose-sensing receptor, as well as processes that lead ultimately to changes in cell growth and metabolism.

Sign in / Sign up

Export Citation Format

Share Document