Summary: Regulator of G protein signaling domain

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Wikipedia: Regulator of G protein signalling
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Regulator of G protein signalling Edit Wikipedia article

Regulator of G-Protein Signaling Domain

Structures of active conformations of Gi alpha 1.^[1]

Identifiers

Symbol

RGS

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Regulators of G protein signaling (or RGS) are protein structural domains that activate GTPases for heterotrimeric G-protein alpha-subunits.

RGS are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways.^[2] Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit (IPR001019), which can then bind the beta-gamma dimer (IPR001632 IPR001770) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.

All RGS proteins contain an RGS-box (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are little more than an RGS domain, while others also contain additional domains that confer further functionality.^[3]

RGS domains can be found within the same protein in combination with a variety of other domains, including: DEP for membrane targeting (IPR000591), PDZ for binding to GPCRs (IPR001478), PTB for phosphotyrosine-binding (IPR006020), RBD for Ras-binding (IPR003116), GoLoco for guanine nucleotide inhibitor activity (IPR003109), PX for phosphoinositide-binding (IPR001683), PXA that is associated with PX (IPR003114), PH for phosphatidylinositol-binding (IPR001849), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (IPR001770).^[4] Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.

[edit] Examples

Human proteins containing this domain include:

ADRBK1, ADRBK2, AXIN1, AXIN2
GRK1, GRK4, GRK5, GRK6, GRK7,
RGS1, RGS2, RGS3, RGS4, RGS5, RGS6, RGS7, RGS8, RGS9, RGS10, RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS20, RGS21
RK
SNX13

[edit] See also

GTP-binding protein regulators:

GEF
GAP

[edit] References

^ Coleman DE, Berghuis AM, Lee E, Linder ME, Gilman AG, Sprang SR (September 1994). "Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis". Science 265 (5177): 1405â12. doi:10.1126/science.8073283. PMID 8073283.
^ De Vries L, Farquhar MG, Zheng B, Fischer T, Elenko E (2000). "The regulator of G protein signaling family". Annu. Rev. Pharmacol. Toxicol. 40: 235â271. doi:10.1146/annurev.pharmtox.40.1.235. PMID 10836135.
^ Burchett SA (2000). "Regulators of G protein signaling: a bestiary of modular protein binding domains". J. Neurochem. 75 (4): 1335â1351. doi:10.1046/j.1471-4159.2000.0751335.x. PMID 10987813.
^ Dohlman HG, Chasse SA (2003). "RGS proteins: G protein-coupled receptors meet their match". Assay Drug Dev Technol 1 (2): 357â364. doi:10.1089/154065803764958649. PMID 15090201.

[edit] Further reading

Tesmer, JJ; Berman, DM; Gilman, AG; Sprang, SR (1997). "Structure of RGS4 bound to AlF4--activated G(i alpha1): Stabilization of the transition state for GTP hydrolysis". Cell 89 (2): 251â61. PMID 9108480.
Dohlman HG, Apaniesk D, Chen Y, Song J, Nusskern D (July 1995). "Inhibition of G-protein signaling by dominant gain-of-function mutations in Sst2p, a pheromone desensitization factor in Saccharomyces cerevisiae". Mol. Cell. Biol. 15 (7): 3635â43. PMC 230601. PMID 7791771.
Watson N, Linder ME, Druey KM, Kehrl JH, Blumer KJ (September 1996). "RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits". Nature 383 (6596): 172â5. doi:10.1038/383172a0. PMID 8774882.
Berman DM, Wilkie TM, Gilman AG (August 1996). "GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits". Cell 86 (3): 445â52. doi:10.1016/S0092-8674(00)80117-8. PMID 8756726.
De Vries L, Mousli M, Wurmser A, Farquhar MG (December 1995). "GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain". Proc. Natl. Acad. Sci. U.S.A. 92 (25): 11916â20. doi:10.1073/pnas.92.25.11916. PMC 40514. PMID 8524874.
Dohlman HG (October 2009). "RGS proteins: The early days". Prog Mol Biol Transl Sci. Progress in Molecular Biology and Translational Science 86: 1â14. doi:10.1016/S1877-1173(09)86001-8. ISBN 9780123747594. PMID 20374711.

[edit] External links

[1] in PROSITE

GTP-binding protein regulators

GTPase activating protein

Monomeric	Chimerin (CHN1, CHN2) Â· RasGAP (NF1, IQGAP) Â· Tuberous sclerosis protein (TSC1, TSC2)

Heterotrimeric	Regulator of G protein signalling: RGS1, RGS2, RGS3, RGS4, RGS5, RGS6, RGS7, RGS8, RGS9, RGS10, RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS20, RGS21

Guanine nucleotide exchange factor

EIF2B Â· Son of Sevenless Â· Ras-GRF1

FGD: FGD1 Â· FGD2 Â· FGD3 Â· FGD4

ALS2 Â· SIL1 Â· IQSEC2

Other

Guanosine nucleotide dissociation inhibitors

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

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RGS family members are GTPase-activating proteins for heterotrimeric G-protein alpha-subunits.

Literature references

Tesmer JJ, Berman DM, Gilman AG, Sprang SR; , Cell 1997;89:251-261.: Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. PUBMED:9108480 EPMC:9108480
Dohlman HG, Apaniesk D, Chen Y, Song J, Nusskern D; , Mol Cell Biol 1995;15:3635-3643.: Inhibition of G-protein signaling by dominant gain-of-function mutations in Sst2p, a pheromone desensitization factor in Saccharomyces cerevisiae. PUBMED:7791771 EPMC:7791771
Watson N, Linder ME, Druey KM, Kehrl JH, Blumer KJ; , Nature 1996;383:172-175.: RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits. PUBMED:8774882 EPMC:8774882
Berman DM, Wilkie TM, Gilman AG; , Cell 1996;86:445-452.: GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. PUBMED:8756726 EPMC:8756726
De Vries L, Mousli M, Wurmser A, Farquhar MG; , Proc Natl Acad Sci U S A 1995;92:11916-11920.: GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain. PUBMED:8524874 EPMC:8524874
Anantharaman V, Abhiman S, de Souza RF, Aravind L;, Gene. 2011;475:63-78.: Comparative genomics uncovers novel structural and functional features of the heterotrimeric GTPase signaling system. PUBMED:21182906 EPMC:21182906

External database links

HOMSTRAD:	RGS
PANDIT:	PF00615
Pseudofam:	PF00615
SCOP:	1gia
SMART:	RGS
SYSTERS:	RGS

This tab holds annotation information from the InterPro database.

InterPro entry IPR000342

RGS (Regulator of G Protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways [PUBMED:10836135]. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit (INTERPRO), which can then bind the beta-gamma dimer (INTERPRO, INTERPRO) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.

All RGS proteins contain an 'RGS-box' (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are comprised of little more than an RGS domain, while others also contain additional domains that confer further functionality [PUBMED:10987813]. RGS domains can be found in conjunction with a variety of domains, including: DEP for membrane targeting (INTERPRO), PDZ for binding to GPCRs (INTERPRO), PTB for phosphotyrosine-binding (INTERPRO), RBD for Ras-binding (INTERPRO), GoLoco for guanine nucleotide inhibitor activity (INTERPRO), PX for phosphatidylinositol-binding (INTERPRO), PXA that is associated with PX (INTERPRO), PH for stimulating guanine nucleotide exchange (INTERPRO), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (INTERPRO) [PUBMED:15090201]. Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Biological process

termination of G-protein coupled receptor signaling pathway (GO:0038032)

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan RGS (CL0272), which contains the following 2 members:

RGS RGS-like

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

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FASTA
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You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (74)	Full (4150)	Representative proteomes				NCBI (3808)	Meta (11)
	Seed (74)	Full (4150)	RP15 (835)	RP35 (1141)	RP55 (1805)	RP75 (2509)	NCBI (3808)	Meta (11)
Jalview	View	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (74)	Full (4150)	Representative proteomes				NCBI (3808)	Meta (11)
	Seed (74)	Full (4150)	RP15 (835)	RP35 (1141)	RP55 (1805)	RP75 (2509)	NCBI (3808)	Meta (11)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (74)	Full (4150)	Representative proteomes				NCBI (3808)	Meta (11)
	Seed (74)	Full (4150)	RP15 (835)	RP35 (1141)	RP55 (1805)	RP75 (2509)	NCBI (3808)	Meta (11)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

SMART

Previous IDs:

none

Type:

Domain

Author:

Ponting C, Schultz J, Bork P

Number in seed:

74

Number in full:

4150

Average length of the domain:

120.60 aa

Average identity of full alignment:

21 %

Average coverage of the sequence by the domain:

22.88 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.0	21.0
Trusted cut-off	21.0	21.0
Noise cut-off	20.9	20.9

Model length:

118

Family (HMM) version:

14

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

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Interactions

There are 4 interactions for this family. More...

Pkinase G-gamma RGS WD40

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the RGS domain has been found. There are 83 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: RGS (PF00615)

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