scholarly journals When Heterotrimeric G Proteins Are Not Activated by G Protein-Coupled Receptors: Structural Insights and Evolutionary Conservation

Biochemistry ◽  
2017 ◽  
Vol 57 (3) ◽  
pp. 255-257 ◽  
Author(s):  
Vincent DiGiacomo ◽  
Arthur Marivin ◽  
Mikel Garcia-Marcos
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Evolutionary Conservation ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
G Protein Coupled ◽  
Structural Insights

scholarly journals Signaling from G Protein-coupled Receptors to ERK5/Big MAPK 1 Involves Gαqand Gα12/13Families of Heterotrimeric G Proteins

2000 ◽  
Vol 275 (28) ◽  
pp. 21730-21736 ◽  
Author(s):  
Shigetomo Fukuhara ◽  
Maria Julia Marinissen ◽  
Mario Chiariello ◽  
J. Silvio Gutkind
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
G Protein Coupled

scholarly journals II. Regulation of neuropeptide receptors in enteric neurons

1998 ◽  
Vol 274 (5) ◽  
pp. G792-G796
Author(s):  
Karen McConalogue ◽  
Nigel W. Bunnett
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Target Cell ◽  
Biological Effects ◽  
G Protein Coupled Receptors ◽  
Enteric Neurons ◽  
Heterotrimeric G Proteins ◽  
High Affinity ◽  
Neuropeptide Receptors ◽  
G Protein Coupled

Neuropeptides exert their diverse biological effects by interacting with G protein-coupled receptors (GPCRs). In this review we address the question, What regulates the ability of a target cell, in particular a neuron, to respond to a neuropeptide? Available evidence from studies of many GPCRs in reconstituted systems and transfected cell lines indicates that much of this regulation occurs at the level of the receptor and serves to alter the capacity of the receptor to bind ligands with high affinity and to couple to heterotrimeric G proteins. Although some of the knowledge gained from these studies is applicable to the regulation of neuropeptide receptors on neurons, at present there are far more questions than answers.

scholarly journals Structural insights into emergent signaling modes of G protein–coupled receptors

2020 ◽  
Vol 295 (33) ◽  
pp. 11626-11642 ◽  
Author(s):  
Ieva Sutkeviciute ◽  
Jean-Pierre Vilardaga
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Prescription Drugs ◽  
Helical Structure ◽  
G Protein Coupled Receptors ◽  
Gpcr Signaling ◽  
Gpcr Activation ◽  
Endosomal Membranes ◽  
G Protein Coupled ◽  
Structural Insights

G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes.

scholarly journals PRECOG: PREdicting COupling probabilities of G-protein coupled receptors

2019 ◽  
Vol 47 (W1) ◽  
pp. W395-W401 ◽  
Author(s):  
Gurdeep Singh ◽  
Asuka Inoue ◽  
J Silvio Gutkind ◽  
Robert B Russell ◽  
Francesco Raimondi
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Protein Sequence ◽  
Web Server ◽  
Structural Features ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
Eukaryotic Organism ◽  
Extracellular Stimuli ◽  
G Protein Coupled

Abstract G-protein coupled receptors (GPCRs) control multiple physiological states by transducing a multitude of extracellular stimuli into the cell via coupling to intra-cellular heterotrimeric G-proteins. Deciphering which G-proteins couple to each of the hundreds of GPCRs present in a typical eukaryotic organism is therefore critical to understand signalling. Here, we present PRECOG (precog.russelllab.org): a web-server for predicting GPCR coupling, which allows users to: (i) predict coupling probabilities for GPCRs to individual G-proteins instead of subfamilies; (ii) visually inspect the protein sequence and structural features that are responsible for a particular coupling; (iii) suggest mutations to rationally design artificial GPCRs with new coupling properties based on predetermined coupling features.

scholarly journals DAPLE protein inhibits nucleotide exchange on Gαs and Gαq via the same motif that activates Gαi

2020 ◽  
Vol 295 (8) ◽  
pp. 2270-2284 ◽  
Author(s):  
Arthur Marivin ◽  
Marcin Maziarz ◽  
Jingyi Zhao ◽  
Vincent DiGiacomo ◽  
Isabel Olmos Calvo ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Birth Defects ◽  
High Frequency ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
Nucleotide Exchange ◽  
Cytoplasmic Proteins ◽  
G Protein Coupled

Besides being regulated by G-protein–coupled receptors, the activity of heterotrimeric G proteins is modulated by many cytoplasmic proteins. GIV/Girdin and DAPLE (Dvl-associating protein with a high frequency of leucine) are the best-characterized members of a group of cytoplasmic regulators that contain a Gα-binding and -activating (GBA) motif and whose dysregulation underlies human diseases, including cancer and birth defects. GBA motif–containing proteins were originally reported to modulate G proteins by binding Gα subunits of the Gi/o family (Gαi) over other families (such as Gs, Gq/11, or G12/13), and promoting nucleotide exchange in vitro. However, some evidence suggests that this is not always the case, as phosphorylation of the GBA motif of GIV promotes its binding to Gαs and inhibits nucleotide exchange. The G-protein specificity of DAPLE and how it might affect nucleotide exchange on G proteins besides Gαi remain to be investigated. Here, we show that DAPLE's GBA motif, in addition to Gαi, binds efficiently to members of the Gs and Gq/11 families (Gαs and Gαq, respectively), but not of the G12/13 family (Gα12) in the absence of post-translational phosphorylation. We pinpointed Met-1669 as the residue in the GBA motif of DAPLE that diverges from that in GIV and enables better binding to Gαs and Gαq. Unlike the nucleotide-exchange acceleration observed for Gαi, DAPLE inhibited nucleotide exchange on Gαs and Gαq. These findings indicate that GBA motifs have versatility in their G-protein–modulating effect, i.e. they can bind to Gα subunits of different classes and either stimulate or inhibit nucleotide exchange depending on the G-protein subtype.

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