Summary: GoLoco motif

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Wikipedia: GoLoco motif
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GoLoco motif Edit Wikipedia article

GoLoco motif

crystal structure of human g[alpha]i1 bound to the goloco motif of rgs14

Identifiers

Symbol

GoLoco

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

GoLoco motif is a protein structural motif.^[1]^[2]^[3]

In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolyzing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to the receptor, GDP is displaced from G-alpha and GTP is bound. The GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP-bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see PDOC50132), and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators.^[1]^[4] acts as a GDI on G-alpha(i).^[2]^[5]

[edit] Structure

The crystal structure of the GoLoco motif in complex with G-alpha(i) has been solved.^[6] It consists of three small alpha helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see PDOC50238). This addition of an arginine in the binding pocket affects the interaction of GDP with G-alpha and therefore is certainly important for the GoLoco GDI activity.^[6]

[edit] Examples

Some proteins known to contain a GoLoco motif are listed below:

Mammalian regulators of G-protein signaling 12 and 14 (RGS12 and RGS14), multifaceted signal transduction regulators.
Loco, the drosophila RGS12 homologue.
Mammalian Purkinje-cell protein-2 (Pcp2). It may function as a cell-type specific modulator for G protein-mediated cell signaling. It is uniquely expressed in cerebellar Purkinje cells and in retinal bipolar neurons.
Eukaryotic Rap1GAP. A GTPase activator for the nuclear ras-related regulatory protein RAP-1A.
Drosophila protein Rapsynoid (also known as Partner of Inscuteable, Pins) and its mammalian homologues, AGS3 and LGN. They form a G-protein regulator family that also contains TPR repeats.

Human proteins containing this domain include:

[edit] References

^ ^a ^b Siderovski DP, DiversÃ©-Pierluissi M, De Vries L (September 1999). "The GoLoco motif: a Galphai/o binding motif and potential guanine-nucleotide exchange factor". Trends Biochem. Sci. 24 (9): 340â1. PMID 10470031.
^ ^a ^b De Vries L, Fischer T, TronchÃ¨re H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG (December 2000). "Activator of G protein signaling 3 is a guanine dissociation inhibitor for Galpha i subunits". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14364â9. doi:10.1073/pnas.97.26.14364. PMC 18924. PMID 11121039.
^ Kimple RJ, Kimple ME, Betts L, Sondek J, Siderovski DP (April 2002). "Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits". Nature 416 (6883): 878â81. doi:10.1038/416878a. PMID 11976690.
^ Ponting CP (1999). "Raf-like Ras/Rap-binding domains in RGS12- and still-life-like signalling proteins". J. Mol. Med. 77 (10): 695â698. doi:10.1007/s001099900054. PMID 10606204.
^ Artemyev NO, Natochin M, Lester B, Peterson YK, Bernard ML, Lanier SM (2000). "AGS3 inhibits GDP dissociation from galpha subunits of the Gi family and rhodopsin-dependent activation of transducin". J. Biol. Chem. 275 (52): 40981â40985. doi:10.1074/jbc.M006478200. PMID 11024022.
^ ^a ^b Siderovski DP, Kimple RJ, Kimple ME, Betts L, Sondek J (2002). "Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits". Nature 416 (6883): 878â881. doi:10.1038/416878a. PMID 11976690.

This article incorporates text from the public domain Pfam and InterPro IPR003109

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Literature references

Siderovski DP, Diverse-Pierluissi M, De Vries L; , Trends Biochem Sci 1999;24:340-341.: The GoLoco motif: a Galphai/o binding motif and potential guanine-nucleotide exchange factor. PUBMED:10470031 EPMC:10470031
De Vries L, Fischer T, Tronchere H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG; , Proc Natl Acad Sci U S A 2000;97:14364-14369.: Activator of G protein signaling 3 is a guanine dissociation inhibitor for Galpha i subunits. PUBMED:11121039 EPMC:11121039
Kimple RJ, Kimple ME, Betts L, Sondek J, Siderovski DP; , Nature 2002;416:878-881.: Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits. PUBMED:11976690 EPMC:11976690

External database links

PANDIT:	PF02188
Pseudofam:	PF02188
SCOP:	1kjy
SMART:	GoLoco
SYSTERS:	GoLoco

This tab holds annotation information from the InterPro database.

InterPro entry IPR003109

In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolysing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to the receptor, GDP is displaced from G-alpha and GTP is bound. GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see PROSITEDOC), and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators [PUBMED:10470031, PUBMED:10606204] acts as a GDI on G-alpha(i) [PUBMED:11121039, PUBMED:11024022].

The crystal structure of the GoLoco motif in complex with G-alpha(i) has been solved [PUBMED:11976690]. It consists of three small alpha helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see PROSITEDOC). This addition of an arginine in the binding pocket affects the interaction of GDP with G-alpha and therefore is certainly important for the GoLoco GDI activity [PUBMED:11976690].

Some proteins known to contain a GoLoco motif are listed below:

Mammalian regulators of G-protein signalling 12 and 14 (RGS12 and RGS14), multifaceted signal transduction regulators.
Loco, the drosophila RGS12 homologue.
Mammalian Purkinje-cell protein-2 (Pcp2). It may function as a cell-type specific modulator for G protein-mediated cell signalling. It is uniquely expressed in cerebellar Purkinje cells and in retinal bipolar neurons.
Eukaryotic Rap1GAP. A GTPase activator for the nuclear ras-related regulatory protein RAP-1A.
Drosophila protein Rapsynoid (also known as Partner of Inscuteable, Pins) and its mammalian homologues AGS3 and LGN. They form a G-protein regulator family that also contains TPR repeats.

Gene Ontology

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

Molecular function	GTPase regulator activity (GO:0030695)
Biological process	signal transduction (GO:0007165)

Domain organisation

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

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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:

Selex
Stockholm
FASTA
MSF

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 (46)	Full (1105)	Representative proteomes				NCBI (983)	Meta (0)
	Seed (46)	Full (1105)	RP15 (104)	RP35 (151)	RP55 (308)	RP75 (542)	NCBI (983)	Meta (0)
Jalview	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 (46)	Full (1105)	Representative proteomes				NCBI (983)	Meta (0)
	Seed (46)	Full (1105)	RP15 (104)	RP35 (151)	RP55 (308)	RP75 (542)	NCBI (983)	Meta (0)
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 (46)	Full (1105)	Representative proteomes				NCBI (983)	Meta (0)
	Seed (46)	Full (1105)	RP15 (104)	RP35 (151)	RP55 (308)	RP75 (542)	NCBI (983)	Meta (0)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download
Gzipped	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:

Alignment kindly provided by SMART

Previous IDs:

none

Type:

Motif

Author:

SMART

Number in seed:

46

Number in full:

1105

Average length of the domain:

22.80 aa

Average identity of full alignment:

44 %

Average coverage of the sequence by the domain:

8.24 %

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	20.7	20.7
Trusted cut-off	21.0	21.2
Noise cut-off	20.5	20.6

Model length:

23

Family (HMM) version:

12

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

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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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The tree shows the occurrence of this domain across different species. More...

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:

show/hide the summary boxes
highlight species that are represented in the seed alignment
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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 GoLoco domain has been found. There are 10 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: GoLoco (PF02188)

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