Proteopedia - User contributions [en]

Regulator of G protein signaling

2015-08-06T09:36:56Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi 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 Gαi 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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-06T09:34:47Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/5'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-06T09:14:59Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/3'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-06T09:10:28Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-06T08:51:24Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. Another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might interact with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:41:39Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:36:56Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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 Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:29:55Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:21:02Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 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/4'>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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:12:48Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/4'>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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:09:42Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/3'>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.

== Gαi1 Structural highlights ==
Gαi1 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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T12:01:14Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/3'>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.

== Gαi1 Structural highlights ==
Gαi1 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-rgs4/21'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T11:38:38Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/3'>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.

== Gαi1 Structural highlights ==
Gαi1 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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T11:27:33Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/3'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-08-04T11:22:41Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/8'> 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/2'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>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 Gαi is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-15T12:01:40Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of 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 Gαo is <scene name='70/701447/Gi-rgs4_arg166/2'>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.
</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T14:07:24Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of 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 Gαo is <scene name='70/701447/Gi-rgs4-arg166/1'>Arg-166</scene> shown as blue sticks which contacts the side chains of Glu-116 which is located in the helical domain of Gα, shown as magenta sticks.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T14:06:52Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of Lys-180, Gln-204, and Glu-207 shown as green, magenta, and red sticks respectively. A unique modulatory RGS4 residue that interacts with Gαo is <scene name='70/701447/Gi-rgs4-arg166/1'>Arg-166</scene> shown as blue sticks which contacts the side chains of Glu-116 which is located in the helical domain of Gα, shown as magenta sticks.<ref name="Tesmer97" />

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:58:51Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of Lys-180, Gln-204, and Glu-207 shown as green, magenta, and red sticks respectively. A unique modulatory RGS4 residue that interacts with the helical domain of Gαo is <scene name='70/701447/Gi-rgs4-arg166/1'>Arg-166</scene> shown as blue sticks which contacts the side chains of Glu-116 shown as magenta sticks.<ref name="Tesmer97" />

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:44:31Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of Lys-180, Gln-204, and Glu-207 shown as green, magenta, and red sticks respectively. A unique modulatory RGS4 residue that interacts with the helical domain of Gαo is Arg-166 shown as........ which contacts the side chains of Glu-116 shown as ........... sticks.<ref name="Tesmer97" />

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:40:13Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>Asn-128</scene> shown as blue sticks, which contacts the side chains of Lys-180, Gln-204, and Glu-207 shown as green, magenta, and red sticks respectively. A unique modulatory RGS4 residue that projects into .......... of Gαi is Arg-166 shown as........ which contacts the side chains of shown as ........... sticks respectively.<ref name="Tesmer97" />

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:23:32Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively. <ref name="Tesmer97" />

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:22:25Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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 Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:21:26Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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>PMID: 21685921</ref> For example, one important conserved RGS4 residue that projects into the active site of Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:20:57Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 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/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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" />

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 Gαi 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>PMID: 21685921</ref> For example, one important conserved RGS4 residue that projects into the active site of Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:19:09Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 residues: 176–184, 201–215, and 233–241, respectively. <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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>PMID: 21685921</ref>

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 Gαi 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>PMID: 21685921</ref> For example, one important conserved RGS4 residue that projects into the active site of Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-14T13:17:36Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there 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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 residues: 176–184, 201–215, and 233–241, respectively. <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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>PMID: 21685921</ref>

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 Gαi 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>PMID: 21685921</ref> For example, one important conserved RGS4 residue that projects into the active site of Gαi is <scene name='70/701447/Gi-rgs4-asn128/1'>r-Asn-128</scene> shown as blue sticks, which contacts the side chains of a-Lys-180, a-Gln-204, and a-Glu-207 shown as green, magenta, and red sticks respectively.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-13T14:17:46Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 residues: 176–184, 201–215, and 233–241, respectively. <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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>PMID: 21685921</ref>

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 Gαi 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. For example, one important RGS4 residue that projects into the active site of Gαi is r-Asn-128, which contacts the side chains of a-Gln-204, a-Ser-206, and a-Glu-207.<ref>PMID: 21685921</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-13T13:57:14Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 residues: 176–184, 201–215, and 233–241, respectively. <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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>PMID: 21685921</ref>

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 Gαi 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>PMID: 21685921</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-07-13T13:49:36Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' 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 classified to 4 groups based on there sequence identity. The first two groups, Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily. another group, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily. The last subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>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 + Pi).

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 Gi and Gq 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.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

== RGS4 Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> 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/1'>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.

== Gαi1 Structural highlights ==
Gαi1 subunits adopt a conserved fold of <scene name='70/701447/All-helical-domain/6'>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-rgs4/20'>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+2 bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1 residues: 176–184, 201–215, and 233–241, respectively. <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues located in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> (RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface) contribute to RGS-G proteins interaction. Based on energy calculation and experimental validation of RGS-Gα complexes from Gαi 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/1'>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>PMID: 21685921</ref>

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/3'>Gα residues</scene> from Gαi 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>PMID: 21685921</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-25T15:41:37Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride(AlF-4).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12/13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.

== Structural highlights ==
1AGR is a complex of RGS4 and Gαi1 proteins defined by X-ray crystallographic analysis.
<scene name='70/701447/Rgs4_monomer/5'> The RGS4 domain </scene> corresponds to an array of nine α-helices that fold into two small subdomains, both subdomains are required for it's GAP activity. 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.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> , a helical domain of six α helices shown as blue cartoon and a GTPase domain shown in gray cartoons. 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-rgs4/20'>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+2, bound in the active site of Gαi1 is shown as a ball-and-stick model. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

== RGS-G proteins interactions ==
Many RGS protein residues in the vicinity of the <scene name='70/701447/Rgs4-ga_interface/3'>RGS domain–Gα interface</scene> contribute to RGS-G proteins interaction, RGS protein shown as wheat cartoon and Gαi1 subunit shown as white surface. These residues are classified into two major groups. First group is Significant & Conserved residues 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 second group is putative Modulatory residues shown as purple spheres that are located mostly at the periphery of the interface where they contribute to Gα subunit's recognition.<ref>PMID: 21685921</ref>

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/1'>Gα residues</scene> that interact specifically with RGS proteins are highly conserved (red spheres). Gα Residues located on Gα switch regions interact with Significant & Conserved RGS residues. This makes sense 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.

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-19T13:16:03Z

Denise Salem:

Regulator of G protein signaling

2015-05-19T10:34:43Z

Denise Salem:

Regulator of G protein signaling

2015-05-18T12:47:35Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but can't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-18T12:44:21Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-18T12:43:50Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-18T12:41:05Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>

In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-18T10:20:30Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>
In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-18T10:20:12Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
</imagemap>
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>PMID: 21685921</ref>
In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-17T09:04:12Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>
In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/16'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-17T08:55:19Z

Denise Salem:

==Regulator of G protein signaling (RGS) interactions with G proteins – RGS4-Gαi as a model structure.==
<StructureSection load='1agr' size='340' side='right' caption='RGS4-Gα complex' scene='70/701447/Gi-rgs4/9' pspeed='8'>
== 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 + Pi), which can be mimicked by Gα-GDP bound with the planar ion aluminum tetrafluoride (AlF4−).

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. About 20 ‘canonical’ RGS proteins can in theory downregulate any of the 16 activated Gα subunits, although in practice they interact only with members of the Gi and Gq families. In these proteins, the ~120-residue RGS homology domain functions as a GTPase-activating protein (GAP) for GTP-bound Gα subunits.

<imagemap>
Image:Kosloff-NSMB2011-Fig1b.jpg|350px|family of canonical RGS proteins
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
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>PMID: 21685921</ref>
In addition to these domains, diverse proteins subfamilies that include the ~120-residue RGS homology domain bear 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.

== 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.
<imagemap>
Image:Ga_family_figure1-heterotrimeric_G-protein-short_history_06.jpg|300px|Homology of mammalian G-protein α-subunits.
poly 131 45 213 41 210 110 127 109 [[2zv4]]
</imagemap>
Phylogenetic tree of mammalian G-protein α-subunits classified to 4 groups based on there sequence identity.<ref>PMID: 16402120</ref> Gαi and Gαq families have selectivity towards The RGS members of R4-subfamily and R12-subfamily, Gαz subunits were suggested to have selectivity for the RGS members of RZ-subfamily . The other two subfamilies Gαs and Gα12,13 might doing interaction with diverse proteins subfamilies that include the ~120-residue RGS homology domain but cann't interact with canonical RGS members.

== Structural highlights ==
The structure of the RGS domain was defined by X-ray crystallographic analysis of a complex of RGS4 and Gαi1.
1AGR is a tetramer structure of two identical duplicate crystal complex of <scene name='70/701447/Gi-rgs4/11'>RGS4- Gαi1</scene> (tetramer excess stability of crystal structure) GDP–Mg+2, bound in the active site of Gαi1 is shown as a ball-and-stick model.
<scene name='70/701447/Rgs_monomer/13'>Monomer structure of RGS4</scene> in green cartoon diagram: The RGS4 domain corresponds to an array of nine α-helices that fold into two small subdomains. The terminal subdomain contains the N and C termini of the box and is formed by α1, α2, α3, α8, and α9. Helices α1 and α9 lie in antiparallel orientation, juxtaposing the N and C termini of the box. The larger bundle subdomain, formed by α4, α5, α6, and α7, is a classic right-handed, antiparallel four-helix bundle. Both subdomains are required for GAP activity.

Gαi1 subunits adopt a conserved fold composed of <scene name='70/701447/All-helical-domain/6'>α helical domain</scene> (deepsky blue cartoon), a helical domain of six α helices and <scene name='70/701447/Gtpase_domain/2'>a GTPase domain</scene> (cornflower blue cartoon).The GTPase domain hydrolyzes GTP and provides most of Gα's binding surfaces for Gβγ, receptors, effectors and RGS proteins. The GTPase domain contains three flexible regions designated <scene name='70/701447/Gi-s1/6'>switch-I</scene> presented as blue sticks, <scene name='70/701447/Gi-s2/3'>switch-II</scene> presented as magenta sticks and <scene name='70/701447/Gi-s3/2'>switch-III</scene> presented as green sticks that change conformation in response to GTP binding and hydrolysis. The three switch regions of Gαi1: residues 176–184, 201–215, and 233–241, respectively . <ref>PMID: 9108480</ref>

</StructureSection>
== References ==

<references/>

Regulator of G protein signaling

2015-05-14T10:07:12Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T10:06:53Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T10:05:30Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T10:05:13Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T10:04:50Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T10:04:16Z

Denise Salem:

File:Ga family figure1-heterotrimeric G-protein-short history 06.jpg

2015-05-14T10:02:17Z

Denise Salem: Homology of mammalian G-protein α-subunits.

Homology of mammalian G-protein α-subunits.

Regulator of G protein signaling

2015-05-14T09:45:26Z

Denise Salem:

Regulator of G protein signaling

2015-05-14T09:40:50Z

Denise Salem: