View source for Regulator of G protein signaling

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gα<sub>i</sub> as a model structure.==
<StructureSection load='' size='340' side='right' caption='Rat regulator of G-protein signalling 4 (red) complex with guanine nucleotide-binding protein α subunit (grey) (PDB code [[1agr]])' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== Heterotrimeric G-proteins family ==
Human heterotrimeric G-proteins are derived from 35 genes: 16 encoding α subunits, 5 β and 14 γ subunits.
The α subunits function as guanine nucleotide on-off switches, mechanistically similar to other G-proteins that are enzymatic GTPases. 
G-proteins interact with diverse protein partners, such as G-protein coupled receptors (GPCRs), downstream effectors, and other proteins. 
One important G-protein interaction is with members of the RGS protein family. This interaction occurs when the G-protein alpha subunit is activated, and depends on the Gα class, which in turn depends on their sequence that classifies them into several sub-types. Based on the Phylogenetic tree of mammalian G-protein, G-protein α-subunits are classified to 4 groups based on their sequence identity. The first two groups, Gα<sub>i</sub> and Gα<sub>q</sub> families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gα<sub>z</sub> subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gα<sub>s</sub> and Gα<sub>12/13</sub> might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.

[[Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.]]

Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on their sequence identity.<ref name="Milligan2006">PMID: 16402120</ref> 

== RGS proteins ==
'''Regulator of G-proteins signaling''' (RGS) proteins play a critical role in many G protein-dependent signaling pathways. Thus, RGS proteins have been implicated in a wide range of pathologies, including cancer, hypertension, arrhythmias, drug abuse and schizophrenia. RGS proteins ‘turn off’ heterotrimeric (αβγ) G-proteins and thereby determine the duration of G protein–mediated signaling events. Therefore, RGS proteins function as GTPase Activating Proteins (GAPs), and this GAP activity is mediated by allosteric interactions.
RGS proteins are selective for binding to the transition state of Gα(GTP → GDP + P<sub>i</sub>).

Like many signaling proteins, RGS proteins comprise a large and diverse family. In human genome, Thirty-seven RGS proteins are encoded by gene loci; this collection of related proteins has been divided into 10 different subfamilies based on the relatedness of their RGS domain sequence and their multiple domain architectures. The major subfamily contains About 20 ‘canonical’ RGS proteins that can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the G<sub>i</sub> and G<sub>q</sub> families.                                             In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits. In addition to these domains, diverse proteins subfamilies include additional protein-protein interaction domains beyond their signature RGS domain with Gα GAP activity. R7-subfamily members share a multi-domain protein architecture composed of DEP and GGL domains on the N-terminal side of the RGS domain. R12-subfamily members possess a tandem repeat of Ras binding domains (RBDs) and a single GoLoco motif.

[[Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins]]

Phylogenetic tree of 19 human RGS domains. 
RGS proteins whose activity was tested are colored by their GAP activity, RGS proteins with high GAP activity (green), RGS proteins with low but discernible activities (purple) and RGS2 had no measurable activity (red).
<ref name="Mickey2011">PMID: 21685921</ref>

== Various RGSs and their functions ==

*'''RGS1''' selectively regulates gut T cell trafficking and colitis potential<ref>PMID:21795595</ref>.<br />
*'''RGS2''' regulates airway hyper responsiveness related to asthma<ref>PMID:25368964</ref>.<br />
*'''RGS3''' is associated with glioma cell motility<ref>PMID:15055445</ref>.<br />
*'''RGS4''' is associated with schizophrenia<ref>PMID:15274033</ref>.<br />
*'''RGS5''' controls blood pressure homeostasis<ref>PMID:23303165</ref>.<br />
*'''RGS6''' promotes anxiety and depression<ref>PMID:24421401</ref>.<br />
*'''RGS9-1''' mediates G protein function in photoreceptors<ref>PMID:11601986</ref>.<br />
*'''RGS10''' negatively regulates cardia remodeling<ref>PMID:26573707</ref>.<br />
*'''RGS12''' regulates osteoclast differentiation<ref>PMID:25909889</ref>.<br />
*'''RGS14''' is an selective Hras effector <ref>PMID:19319189</ref>.<br />
*'''RGS16''' inhibits hepatic fatty acid oxidation<ref>PMID:21357625</ref>.<br />
*'''RGS17''' is a negative modulator of G protein-coupled receptor signaling in human cancers<ref>PMID:26928451</ref>.<br />
*'''RGS18''' regulates platelet aggregation and thrombosis<ref>PMID:25969426</ref>.<br />

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gα<sub>i1</sub> proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/10'> The RGS4 domain </scene> corresponds to an array of nine α-helices: α1, α2, α3, α4, α5 and α6 helices are colored in blue, aqua, yellow, coral, magenta and dark green respectively, while helices α7, α8 and α9 are colored red. The 3D structure of RGS4 protein fold into <scene name='70/701447/Rgs4_subdomains/5'>two small subdomains</scene>, the terminal subdomain colored magenta, contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9; and the larger bundle subdomain colored cyan formed by α4, α5, α6, and α7. The both two subdomains are required for RGS4 GAP activity. 

== Gα<sub>i1</sub> Structural highlights ==
Gα<sub>i1</sub> subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/7'>α helical domain</scene> that composed of six α helices shown as blue cartoon, and a conserved GTPase domain shown in gray cartoon. The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. <scene name='70/701447/Gi-rgs4/22'>The GTPase domain</scene> contains three flexible regions designated switch-I presented as blue sticks, switch-II presented as magenta sticks and switch-III presented as green sticks that change conformation in response to GTP binding and hydrolysis, GDP–Mg<sup>+2</sup> bound in the active site of Gα<sub>i1</sub> is shown as a ball-and-stick model. The three switch regions of Gα<sub>i1</sub> residues: 176–184, 201–215, and 233–241, respectively. <ref name="Tesmer97">PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/4'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gα<sub>i1</sub> subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gα<sub>i</sub> subfamily members,  these residues classified into two major groups: <scene name='70/701447/Rgs4-ga-sandc-residues/4'>Significant and Conserved residues</scene> shown as red spheres that are located mainly in the center of the RGS domain–Gα interface and have a primary role in accelerating Gα GTPase by stabilizing Gα in an optimal conformation for GTP hydrolysis. Whereas the <scene name='70/701447/Rgs4-ga_modulatory_residues/2'>putative Modulatory residues</scene> shown as purple spheres are located mostly at the periphery of the interface where they contribute to Gα subunit's recognition.<ref name="Mickey2011" />

On the other side, Gα subunits participate in a range of interactions with a variety of other proteins. Therefore, they have interfaces that interact selectively with receptors, effector subfamilies and RGS proteins. However, <scene name='70/701447/Gi-rgs4_interface/4'>Gα residues</scene> from Gα<sub>i</sub> subfamily members that interact specifically with RGS proteins are highly conserved (red spheres). These Gα Residues located on Gα switch regions interact with Significant & Conserved RGS residues because of the pivotal role of the switch regions in GTP hydrolysis that is catalyzed by RGS proteins. On the other hand, Gα residues located in switch regions II and III and multiple residues in the Gα all-helical domain interact with Modulatory RGS residues.<ref name="Mickey2011" /> For example, one important conserved RGS4 residue that projects into the active site of Gα<sub>i</sub> is <scene name='70/701447/Gi-rgs4-asn128/2'>Asn-128</scene> shown as blue sticks, which contacts the side chains of three Gα residues: Lys-180, Gln-204, and Glu-207 shown as green, magenta, and red sticks respectively.<ref name="Tesmer97" /> A unique modulatory RGS4 residue that interacts with Gα<sub>i</sub> is <scene name='70/701447/Gi-rgs4_arg166/6'>Arg-166</scene> shown as blue sticks which forms salt bridge with the positively charged side chain of Glu-116 shown as magenta sticks located in the helical domain of Gα subunit.

==3D structures of regulator of G-protein signaling==
[[Regulator of G-protein signaling 3D structures]]

</StructureSection>

== References ==

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[[Category:Topic Page]]