scholarly journals Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity

PLoS Biology ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. e3001295
Author(s):  
Jesse I. Mobbs ◽  
Matthew J. Belousoff ◽  
Kaleeckal G. Harikumar ◽  
Sarah J. Piper ◽  
Xiaomeng Xu ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Binding Pocket ◽  
Structural Features ◽  
Heterotrimeric G Proteins ◽  
Cck1 Receptor ◽  
Weakly Coupled ◽  
Peptide Agonist ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11–GPCR complexes, the Gq–α5 helix (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from “unwinding” of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.

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 Every Detail Matters. That Is, How the Interaction between Gα Proteins and Membrane Affects Their Function

Membranes ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 222
Author(s):  
Agnieszka Polit ◽  
Paweł Mystek ◽  
Ewa Błasiak
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
G Proteins ◽  
Lipid Membranes ◽  
Signaling Proteins ◽  
Heterotrimeric G Proteins ◽  
Membrane Attachment ◽  
The Individual ◽  
Multicellular Organisms ◽  
G Protein Coupled

In highly organized multicellular organisms such as humans, the functions of an individual cell are dependent on signal transduction through G protein-coupled receptors (GPCRs) and subsequently heterotrimeric G proteins. As most of the elements belonging to the signal transduction system are bound to lipid membranes, researchers are showing increasing interest in studying the accompanying protein–lipid interactions, which have been demonstrated to not only provide the environment but also regulate proper and efficient signal transduction. The mode of interaction between the cell membrane and G proteins is well known. Despite this, the recognition mechanisms at the molecular level and how the individual G protein-membrane attachment signals are interrelated in the process of the complex control of membrane targeting of G proteins remain unelucidated. This review focuses on the mechanisms by which mammalian Gα subunits of G proteins interact with lipids and the factors responsible for the specificity of membrane association. We summarize recent data on how these signaling proteins are precisely targeted to a specific site in the membrane region by introducing well-defined modifications as well as through the presence of polybasic regions within these proteins and interactions with other components of the heterocomplex.

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 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

Science Signaling Podcast for 12 April 2016: G proteins in auriculo-condylar syndrome

2016 ◽  
Vol 9 (423) ◽  
pp. pc9-pc9
Author(s):  
Mikel Garcia-Marcos ◽  
Annalisa M. VanHook
Keyword(s):  
Enzymatic Activity ◽  
G Protein ◽  
G Proteins ◽  
Heterotrimeric G Proteins ◽  
Craniofacial Abnormalities ◽  
Research Article ◽  
Neural Crest Development ◽  
Mutant Forms ◽  
Endothelin Type A Receptor ◽  
G Protein Coupled

AbstractThis Podcast features an interview with Mikel Garcia-Marcos, author of a Research Article that appears in the 12 April 2016 issue of Science Signaling, about how mutations in a G protein cause auriculo-condylar syndrome (ACS). ACS is caused by mutations that affect signaling through the endothelin type A receptor (ETAR) and is characterized by craniofacial abnormalities resulting from defects in neural crest development. ETAR is a G protein–coupled receptor (GPCR) that signals primarily through heterotrimeric G proteins containing Gαq/11, but mutations in Gαi3 are also associated with ACS. Marivin et al. found that ETAR coupled to ACS-associated mutant forms of Gαi3 instead of coupling to Gαq/11. These mutant forms of Gαi3 lacked enzymatic activity and thus blocked ETAR signaling.Listen to Podcast

scholarly journals G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

FEBS Letters ◽  
2020 ◽  
Vol 594 (24) ◽  
pp. 4201-4232
Author(s):  
Nadia Arang ◽  
J. Silvio Gutkind
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
Cancer Drivers ◽  
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 Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mikel Garcia-Marcos ◽  
Kshitij Parag-Sharma ◽  
Arthur Marivin ◽  
Marcin Maziarz ◽  
Alex Luebbers ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Protein Domain ◽  
Heterotrimeric G Proteins ◽  
Protein Activity ◽  
Signal Transducers ◽  
Non Invasive ◽  
Experimental Systems ◽  
Extracellular Stimuli ◽  
G Protein Coupled

Heterotrimeric G-proteins are signal transducers involved in mediating the action of many natural extracellular stimuli and many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we developed LOV2GIVe, an engineered modular protein that allows the activation of heterotrimeric G-proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, that is metazoan opsins, which are light-activated G-protein-coupled receptors (GPCRs). Instead, LOV2GIVe consists of the fusion of a G-protein activating peptide derived from a non-GPCR regulator of G-proteins to a small plant protein domain, such that light uncages the G-protein activating module. Targeting LOV2GIVe to cell membranes allowed for light-dependent activation of Gi proteins in different experimental systems. In summary, LOV2GIVe expands the armamentarium and versatility of tools available to manipulate heterotrimeric G-protein activity.

The Evidence for G-Protein-Coupled Receptors and Heterotrimeric G Proteins in Protozoa and Ancestral Metazoa

Neurosignals ◽  
1998 ◽  
Vol 7 (2) ◽  
pp. 98-108 ◽  
Author(s):  
David C. New ◽  
Joseph T.Y. Wong
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
G Protein Coupled
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