scholarly journals Agonist-specific conformational changes in the yeast alpha-factor pheromone receptor.

1996 ◽  
Vol 16 (9) ◽  
pp. 4818-4823 ◽  
Author(s):  
G Büküşoğlu ◽  
D D Jenness
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Helix ◽  
Intracellular Loop ◽  
Cleavage Rate ◽  
Pheromone Receptor ◽  
Protein Activation ◽  
The Third ◽  
Third Intracellular Loop ◽  
Alpha Factor

The yeast alpha-factor pheromone receptor is a member of the G-protein-coupled receptor family. Limited trypsin digestion of yeast membranes was used to investigate ligand-induced conformational changes in this receptor. The agonist, alpha-factor, accelerated cleavage in the third intracellular loop, whereas the antagonist, desTrp1,Ala3-alpha-factor, reduced the cleavage rate. Thus, the enhanced accessibility of the third intracellular loop is specific to the agonist. alpha-Factor inhibited cleavage weakly at a second site near the cytoplasmic terminus of the seventh transmembrane helix, whereas the antagonist showed a stronger inhibition of cleavage at this site and at another site in the C-terminal domain of the receptor. The alpha-factor-induced conformational changes appeared to be inherent properties of the receptor, as they were retained in G-protein-deficient mutants. Moreover, a mutant receptor (ste2-L236H) that affects the third loop and is defective for G-protein coupling retained the ability to undergo the agonist-induced conformational changes. These results are consistent with a model in which G-protein activation is limited by the availability of specific contacts between the G protein and the third intracellular loop of the receptor. The antagonist appears to promote a distinct conformational state that differs from either the unoccupied or the agonist-occupied state.

scholarly journals A Cyclic Peptide Mimicking the Third Intracellular Loop of the V2Vasopressin Receptor Inhibits Signaling through Its Interaction with Receptor Dimer and G Protein

2004 ◽  
Vol 279 (49) ◽  
pp. 50904-50914 ◽  
Author(s):  
Sébastien Granier ◽  
Sonia Terrillon ◽  
Robert Pascal ◽  
Hélène Déméné ◽  
Michel Bouvier ◽  
...  
Keyword(s):  
G Protein ◽  
Cyclic Peptide ◽  
Intracellular Loop ◽  
The Third ◽  
Third Intracellular Loop ◽  
Receptor Dimer

scholarly journals The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activlation

2022 ◽  
Vol 12 ◽  
Author(s):  
Ian Winfield ◽  
Kerry Barkan ◽  
Sarah Routledge ◽  
Nathan J. Robertson ◽  
Matthew Harris ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Cgrp Receptor ◽  
Intracellular Loop ◽  
Glucagon Receptor ◽  
G Protein Coupled

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

scholarly journals Mutational analysis of the mouse 5-HT7 receptor: importance of the third intracellular loop for receptor-G-protein interaction

FEBS Letters ◽  
1997 ◽  
Vol 412 (2) ◽  
pp. 321-324 ◽  
Author(s):  
Louis A Obosi ◽  
René Hen ◽  
David J Beadle ◽  
Isabel Bermudez ◽  
Linda A King
Keyword(s):  
G Protein ◽  
Protein Interaction ◽  
Mutational Analysis ◽  
Intracellular Loop ◽  
The Third ◽  
Third Intracellular Loop

scholarly journals Recycling ability of the mouse and the human neurotensin type 2 receptors depends on a single tyrosine residue

2002 ◽  
Vol 115 (1) ◽  
pp. 165-173
Author(s):  
Stéphane Martin ◽  
Jean-Pierre Vincent ◽  
Jean Mazella
Keyword(s):  
G Protein ◽  
Kinase Inhibitor ◽  
Site Directed Mutagenesis ◽  
Tyrosine Residue ◽  
Receptor Recycling ◽  
Intracellular Loop ◽  
Structural Element ◽  
The Third ◽  
Third Intracellular Loop ◽  
G Protein Coupled

Receptor recycling plays a key role in the modulation of cellular responses to extracellular signals. The purpose of this work was to identify residues in G-protein coupled neurotensin receptors that are directly involved in recycling. Both the high affinity receptor-1 (NTR1) and the levocabastine-sensitive NTR2 are internalized after neurotensin binding. Here, we show that only the mouse NTR2 recycled to the plasma membrane, whereas the rat NTR1 and the human NTR2 did not. Using site-directed mutagenesis, we demonstrate that tyrosine 237 in the third intracellular loop is crucial for recycling of the mouse NTR2. We show that the mouse NTR2 is phosphorylated on tyrosine residues by NT. This phosphorylation is essential for receptor recycling since the tyrosine kinase inhibitor genistein blocks this process. The absence of recycling observed with the human NTR2 could be completely explained by the presence of a cysteine instead of a tyrosine in position 237. Indeed, substitution of this cysteine by a tyrosine gave a mutant receptor that has acquired the ability to recycle to the cell surface after neurotensin-induced internalization. This work demonstrates that a single tyrosine residue in the third intracellular loop of a G-protein-coupled receptor is responsible for receptor phosphorylation and represents an essential structural element for receptor recycling.

scholarly journals Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death

2015 ◽  
Vol 472 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Kelly E. Burns ◽  
Damien Thévenin
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
G Protein ◽  
Cancer Cell ◽  
Intracellular Loop ◽  
The Third ◽  
Cancer Cell Death ◽  
Third Intracellular Loop ◽  
Ph Dependent ◽  
G Protein Coupled

A pH(Low) Insertion Peptide (pHLIP)-based construct derived from the third intracellular loop (i3) of a G protein-coupled receptor (GPCR) induces a concentration- and pH-dependent cytotoxicity in cancer cells by down-regulating receptor activity. This strategy allows for a more selective intracellular delivery than current approaches.

Structure of the Third Intracellular Loop of the Vasopressin V2 Receptor and Conformational Changes upon Binding to gC1qR

2009 ◽  
Vol 388 (3) ◽  
pp. 491-507 ◽  
Author(s):  
Gaëtan Bellot ◽  
Sébastien Granier ◽  
William Bourguet ◽  
René Seyer ◽  
Rita Rahmeh ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Intracellular Loop ◽  
The Third ◽  
Vasopressin V2 Receptor ◽  
Third Intracellular Loop ◽  
V2 Receptor
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