The Mutation in the N-Terminal Domain of RGS4 Disrupts PA-Conferred Inhibitory Effect on GAP Activity

2003 ◽  
Vol 23 (4) ◽  
pp. 213-224 ◽  
Author(s):  
Ying-Shi Ou-Yang ◽  
Yaping Tu ◽  
Fuyu Yang
Keyword(s):  
G Protein ◽  
Inhibitory Effect ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Site Mutation ◽  
Terminal Domain ◽  
Gtpase Activating Proteins ◽  
N Terminus ◽  
Rgs Domain

Regulator of G protein signaling (RGS) proteins are GTPase-activating proteins (GAP) for G protein α-subunits and are thought to be responsible for rapid deactivation of G protein mediated signaling pathway. In this present study, we demonstrate that PA is the most efficient candidate to inhibit GAP activity of RGS4. The functional significance of N-terminus of RGS4 in respose to PA-granted inhibition on GAP activity has been studied with the site mutation in the N-terminus of RGS4. These site-directed mutations in the N-terminal domain do not severely disrupt its association with liposomes of PA. However, RGS4L23E diminishes the inhibition of GAP activity by PA compared with the wild type RGS4, whereas RGSR22E abrogates the inhibitory effect by PA on GAP activity. The correspondent conformational discrepancy in the RGS domain of these mutants in the presence of PA vesicles was detected from fluorescence experiments. It is suggested that the functional pertinence between the N-terminus and RGS domain may be important to modulate PA-conferred inhibitory effect on its GAP activity.

scholarly journals Regulators of G protein Signaling (RGS) proteins (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (4) ◽  
Author(s):  
Katelin E. Ahlers-Dannen ◽  
Mohammed Alqinyah ◽  
Christopher Bodle ◽  
Josephine Bou Dagher ◽  
Bandana Chakravarti ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Gtp Hydrolysis ◽  
Rgs Domain ◽  
G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [160, 377, 411, 415, 416, 512, 519, 312, 6].

scholarly journals Regulators of G protein Signaling (RGS) proteins (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (5) ◽  
Author(s):  
Katelin E. Ahlers-Dannen ◽  
Mohammed Alqinyah ◽  
Christopher Bodle ◽  
Josephine Bou Dagher ◽  
Bandana Chakravarti ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Gtp Hydrolysis ◽  
Rgs Domain ◽  
G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [183, 411, 446, 450, 451, 558, 566, 345, 9].

scholarly journals Regulators of G protein Signaling (RGS) proteins in GtoPdb v.2021.2

2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Katelin E. Ahlers-Dannen ◽  
Mohammed Alqinyah ◽  
Christopher Bodle ◽  
Josephine Bou Dagher ◽  
Bandana Chakravarti ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Gtp Hydrolysis ◽  
Rgs Domain ◽  
G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [225, 529, 578, 583, 584, 742, 753, 444, 10].

scholarly journals Regulators of G protein Signaling (RGS) proteins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Mohammed Alqinyah ◽  
Christopher Bodle ◽  
Josephine Bou Dagher ◽  
Bandana Chakravarti ◽  
Shreoshi P. Choudhuri ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
G Protein ◽  
G Proteins ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Gtp Hydrolysis ◽  
G Protein Signalling ◽  
Rgs Domain

Regulators of G protein signalling (RGS) proteins display a common RGS domain that interacts with the GTP-bound Gα subunits of heterotrimeric G proteins, enhancing GTP hydrolysis by stabilising the transition state [29, 419, 418], leading to a termination of GPCR signalling. Interactions through protein:protein interactions of many RGS proteins have been identified for targets other than heteromeric G proteins. Sequence analysis of the 20 RGS proteins suggests four families of RGS: RZ, R4, R7 and R12 families. Many of these proteins have been identified to have effects other than through targetting G proteins. Included here is RGS4 for which a number of pharmacological inhibitors have been described.

scholarly journals A finer tuning of G-protein signaling through regulated control of RGS proteins

2012 ◽  
Vol 303 (1) ◽  
pp. H19-H35 ◽  
Author(s):  
Jacob Kach ◽  
Nan Sethakorn ◽  
Nickolai O. Dulin
Keyword(s):  
G Protein ◽  
Cell Function ◽  
Intracellular Localization ◽  
Current Data ◽  
Covalent Modification ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Gtpase Activating Proteins ◽  
G Protein Coupled

Regulators of G-protein signaling (RGS) proteins are GTPase-activating proteins (GAP) for various Gα subunits of heterotrimeric G proteins. Through this mechanism, RGS proteins regulate the magnitude and duration of G-protein-coupled receptor signaling and are often referred to as fine tuners of G-protein signaling. Increasing evidence suggests that RGS proteins themselves are regulated through multiple mechanisms, which may provide an even finer tuning of G-protein signaling and crosstalk between G-protein-coupled receptors and other signaling pathways. This review summarizes the current data on the control of RGS function through regulated expression, intracellular localization, and covalent modification of RGS proteins, as related to cell function and the pathogenesis of diseases.

scholarly journals Endogenous modification of the chemoattractant CXCL5 alters receptor usage and enhances its activity toward neutrophils and monocytes

2021 ◽  
Vol 14 (673) ◽  
pp. eaax3053
Author(s):  
Mieke Metzemaekers ◽  
Anneleen Mortier ◽  
Alessandro Vacchini ◽  
Daiane Boff ◽  
Karen Yu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Chemotactic Activity ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Agonist Activity ◽  
N Terminus ◽  
G Protein Coupled

The inflammatory human chemokine CXCL5 interacts with the G protein–coupled receptor CXCR2 to induce chemotaxis and activation of neutrophils. CXCL5 also has weak agonist activity toward CXCR1. The N-terminus of CXCL5 can be modified by proteolytic cleavage or deimination of Arg9 to citrulline (Cit), and these modifications can occur separately or together. Here, we chemically synthesized native CXCL5(1–78), truncated CXCL5 [CXCL5(9–78)], and the citrullinated (Cit9) versions and characterized their functions in vitro and in vivo. Compared with full-length CXCL5, N-terminal truncation resulted in enhanced potency to induce G protein signaling and β-arrestin recruitment through CXCR2, increased CXCL5-initiated internalization of CXCR2, and greater Ca2+ signaling downstream of not only CXCR2 but also CXCR1. Citrullination did not affect the capacity of CXCL5 to activate classical or alternative signaling pathways. Administering the various CXCL5 forms to mice revealed that in addition to neutrophils, CXCL5 exerted chemotactic activity toward monocytes and that this activity was increased by N-terminal truncation. These findings were confirmed by in vitro chemotaxis and Ca2+ signaling assays with primary human CD14+ monocytes and human THP-1 monocytes. In vitro and in vivo analyses suggested that CXCL5 targeted monocytes through CXCR1 and CXCR2. Thus, truncation of the N-terminus makes CXCL5 a more potent chemoattractant for both neutrophils and monocytes that acts through CXCR1 and CXCR2.

scholarly journals Two Chimeric Regulators of G-protein Signaling (RGS) Proteins Differentially Modulate Soybean Heterotrimeric G-protein Cycle

2012 ◽  
Vol 287 (21) ◽  
pp. 17870-17881 ◽  
Author(s):  
Swarup Roy Choudhury ◽  
Corey S. Westfall ◽  
John P. Laborde ◽  
Naveen C. Bisht ◽  
Joseph M. Jez ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Heterotrimeric G Protein

scholarly journals High-resolution structure of RGS17 suggests a role for Ca2+ in promoting the GTPase-activating protein activity by RZ subfamily members

2019 ◽  
Vol 294 (20) ◽  
pp. 8148-8160 ◽  
Author(s):  
Monita Sieng ◽  
Michael P. Hayes ◽  
Joseph B. O'Brien ◽  
C. Andrew Fowler ◽  
Jon C. Houtman ◽  
...  
Keyword(s):  
G Protein ◽  
General Mechanism ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Protein Activity ◽  
Gtpase Activating Proteins ◽  
Ability To Act ◽  
Binding Surface ◽  
High Resolution Structure ◽  
Resolution Structure

Regulator of G protein signaling (RGS) proteins are negative regulators of G protein–coupled receptor (GPCR) signaling through their ability to act as GTPase-activating proteins (GAPs) for activated Gα subunits. Members of the RZ subfamily of RGS proteins bind to activated Gαo, Gαz, and Gαi1–3 proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca2+-dependent signaling. In contrast to other RGS proteins, little is known about RZ subfamily structure and regulation. Herein, we present the 1.5-Å crystal structure of RGS17, the most complete and highest-resolution structure of an RZ subfamily member to date. RGS17 cocrystallized with Ca2+ bound to conserved positions on the predicted Gα-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca2+ binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca2+ than for Mg2+. Finally, we found that Ca2+ promotes interactions between RGS17 and activated Gα and decreases the Km for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca2+ positively regulates RGS17, which may represent a general mechanism by which increased Ca2+ concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca2+ signaling.

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