{PDOC00594}
{PS00720; RASGEF}
{PS50009; RASGEF_CAT}
{PS50212; RASGEF_NTER}
{BEGIN}
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* Ras guanine-nucleotide exchange factors domain signature and profiles *
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Ras  proteins are membrane-associated molecular switches that bind GTP and GDP
and  slowly  hydrolyze  GTP  to  GDP  [1].  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 [2,3]. The latter proteins
are known as guanine-nucleotide exchange (or releasing) factors (GEFs or GRFs)
(or also as guanine-nucleotide dissociation stimulators (GDSs)).

The  crystal  structure of the GEF region of human Sos1 complexes with Ras has
been solved (see <PDB:1BKD>) [4]. 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 [5].

To identify   Ras-GEF  domains  we  developed  two  profiles.  The  first  one
recognizes the catalytic domain and the second profile is directed against the
N-terminal domain. We also developed a pattern that spans the helical hairpin.

-Consensus pattern: [VI]-P-[FYWVI]-x-[GPSV]-x(2)-[LIVMFYK]-x-[DNE]-[LIVM]-
                    x(13,35)-[IVL]-N-[FYME]-x-K
-Sequences known to belong to this class detected by the profile: ALL,  except
 for BEM2.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the first profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the second profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: April 2003 / Pattern and text revised and profiles added.

[ 1] Bourne H.R., Sanders D.A., McCormick F.
     "The GTPase superfamily: conserved structure and molecular
     mechanism."
     Nature 349:117-127(1991).
     PubMed=1898771; DOI=10.1038/349117a0
[ 2] Boguski M.S., McCormick F.
     "Proteins regulating Ras and its relatives."
     Nature 366:643-654(1993).
     PubMed=8259209; DOI=10.1038/366643a0
[ 3] Downward J.
     "Ras regulation: putting back the GTP."
     Curr. Biol. 2:329-331(1992).
     PubMed=15335949
[ 4] Boriack-Sjodin P.A., Margarit S.M., Bar-Sagi D., Kuriyan J.
     Nature 394:337-343(1998).
[ 5] Albright C.F., Giddings B.W., Liu J., Vito M., Weinberg R.A.
     "Characterization of a guanine nucleotide dissociation stimulator for
     a ras-related GTPase."
     EMBO J. 12:339-347(1993).
     PubMed=8094051

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{END}