Summary: RasGEF domain

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Wikipedia: RasGEF domain
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RasGEF domain Edit Wikipedia article

RasGEF domain

Structure of human H-Ras.^[1]

Identifiers

Symbol

RasGEF

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

RasGEF domain is domain found in the CDC25 family of guanine nucleotide exchange factors for Ras-like small GTPases.

Main article: Ras (protein)

Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP.^[2] The balance between the GTP bound (active) and GDP bound (inactive) states is regulated by the opposite action of proteins activating the GTPase activity and that of proteins which promote the loss of bound GDP and the uptake of fresh GTP.^[3]^[4] The latter proteins are known as guanine-nucleotide dissociation stimulators (GDSs) (or also as guanine-nucleotide releasing (or exchange) factors (GRFs)). Proteins that act as GDS can be classified into at least two families, on the basis of sequence similarities, the CDC24 family (see InterPro: IPR001331) and this CDC25 (RasGEF) family.

The size of the proteins of the CDC25 family range from 309 residues (LTE1) to 1596 residues (sos). The sequence similarity shared by all these proteins is limited to a region of about 250 amino acids generally located in their C-terminal section (currently the only exceptions are sos and ralGDS where this domain makes up the central part of the protein). This domain has been shown, in CDC25 an SCD25, to be essential for the activity of these proteins.

Human proteins containing this domain

KNDC1; PLCE1; RALGDS; RALGPS1; RALGPS2; RAPGEF1; RAPGEF2; RAPGEF3; RAPGEF4; RAPGEF5; RAPGEF6; RAPGEFL1; RASGEF1A; RASGEF1B; RASGEF1C; RASGRF1; RASGRF2; RASGRP1; RASGRP2; RASGRP3; RASGRP4; RGL1; RGL2; RGL3; RGL4/RGR; SOS1; SOS2;

References

^ Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J (July 1998). "The structural basis of the activation of Ras by Sos". Nature. 394 (6691): 337–43. doi:10.1038/28548. PMID 9690470.
^ McCormick F, Bourne HR, Sanders DA (1991). "The GTPase superfamily: conserved structure and molecular mechanism". Nature. 349 (6305): 117–127. doi:10.1038/349117a0. PMID 1898771.
^ McCormick F, Boguski MS (1993). "Proteins regulating Ras and its relatives". Nature. 366 (6456): 643–654. doi:10.1038/366643a0. PMID 8259209.
^ Downward J (1992). "Ras regulation: putting back the GTP". Curr. Biol. 2 (6): 329–331. doi:10.1016/0960-9822(92)90897-J. PMID 15335949.

RasGEF domain Provide feedback

Guanine nucleotide exchange factor for Ras-like small GTPases.

Literature references

Boguski MS, McCormick F; , Nature 1993;366:643-654.: Proteins regulating Ras and its relatives. PUBMED:8259209 EPMC:8259209
Quilliam LA, Khosravi-Far R, Huff SY, Der CJ; , Bioessays 1995;17:395-404.: Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. PUBMED:7786285 EPMC:7786285
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J; , Nature 1993;363:85-88.: Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. PUBMED:8479541 EPMC:8479541
Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J; , Science 1993;260:1953-1955.: The function of GRB2 in linking the insulin receptor to Ras signaling pathways. PUBMED:8316835 EPMC:8316835

Internal database links

SCOOP:

RasGEF_N

External database links

SCOP:	1bkd
SMART:	RasGEF

This tab holds annotation information from the InterPro database.

InterPro entry IPR001895

Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP [ PUBMED:1898771 ] in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. The balance between the GTP bound (active) and GDP bound (inactive) states is regulated by the opposite action of proteins activating the GTPase activity and that of proteins which promote the loss of bound GDP and the uptake of fresh GTP [ PUBMED:8259209 , PUBMED:15335949 ]. The latter proteins are known as guanine-nucleotide exchange (or releasing) factors (GEFs or GRFs) (or also as guanine-nucleotide dissociation stimulators (GDSs)). GEFs catalyze the dissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors [ PUBMED:9438849 , PUBMED:7786285 ].

The crystal structure of the GEF region of human Sos1 complexes with Ras has been solved [ PUBMED:8094051 ]. The structure consists of two distinct alpha helical structural domains: the N-terminal domain which seems to have a purely structural role and the C-terminal domain which is sufficient for catalytic activity and contains all residues that interact with Ras. A main feature of the catalytic domain is the protrusion of a helical hairpin important for the nucleotide-exchange mechanism. The N-terminal domain is likely to be important for the stability and correct placement of the hairpin structure.

Some proteins known to contain a Ras-GEF domain are listed below:

Cdc25 from yeast.
Scd25 from yeast.
Ste6 from fission yeast.
Son of sevenless (gene sos) from Drosophila and mammals.
p140-RAS GRF (cdc25Mm) from mammals. This protein possesses both a domain belonging to the CDC25 family and one belonging to the CDC24 family.
Bud5 from yeast, that may interact with the ras-like protein RSR1/BUD1.
Lte1 from yeast, whose target protein is not yet known.
ralGDS from mammals, which interacts with the ras-like proteins ralA and ralB [ PUBMED:8094051 ].

This entry represents the catalytic domain of the Ras guanine-nucleotide exchange factors.

Gene Ontology

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

Molecular function	guanyl-nucleotide exchange factor activity (GO:0005085)
Biological process	small GTPase mediated signal transduction (GO:0007264)

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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB 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
UniProt: alignment generated by searching the UniProtKB 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.

Reformatting

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

Selex
Stockholm
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 (631)	Full (19334)	Representative proteomes				UniProt (32674)
	Seed (631)	Full (19334)	RP15 (3050)	RP35 (7307)	RP55 (15848)	RP75 (21649)	UniProt (32674)
Jalview	View	View	View	View	View	View	View
HTML	View
PP/heatmap	₁

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

Key: available, not generated, — not available.

Format an alignment

	Seed (631)	Full (19334)	Representative proteomes				UniProt (32674)
	Seed (631)	Full (19334)	RP15 (3050)	RP35 (7307)	RP55 (15848)	RP75 (21649)	UniProt (32674)
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 (631)	Full (19334)	Representative proteomes				UniProt (32674)
	Seed (631)	Full (19334)	RP15 (3050)	RP35 (7307)	RP55 (15848)	RP75 (21649)	UniProt (32674)
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.

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:

Family

Sequence Ontology:

SO:0100021

Author:

Ponting CP

, Schultz J, Bork P

Number in seed:

631

Number in full:

19334

Average length of the domain:

182.10 aa

Average identity of full alignment:

26 %

Average coverage of the sequence by the domain:

18.58 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	23.1	23.1
Trusted cut-off	23.1	23.1
Noise cut-off	23.0	23.0

Model length:

179

Family (HMM) version:

21

Download:

download the raw HMM for this family

Species distribution

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Colour assignments

Archea	Eukaryota
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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
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

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 RasGEF domain has been found. There are 106 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 sequence.

Loading structure mapping...

Family: RasGEF (PF00617)

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