The N-terminal domain of guanine nucleotide exchange factor (GEF) for Ras-like GTPases is also called REM domain (Ras exchanger motif). REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few [, , , , , , , ].The crystal structure of the GEF region of human Sos1 complexes with Ras hasbeen solved []. 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 catalyticactivity and contains all residues that interact with Ras. A main feature ofthe catalytic domain is the protrusion of a helical hairpin important for thenucleotide-exchange mechanism. The N-terminal domain is likely to be importantfor the stability and correct placement of the hairpin structure.This entry represents a domain found in several GEF for Ras-like small GTPases which lies N-terminal to the RasGef (Cdc25-like) domain.
Cell division cycle and apoptosis regulator protein 1 (CCAR1) associates with components of the Mediator and p160 coactivator complexes that play a role as intermediaries transducing regulatory signals from upstream transcriptional activator proteins to basal transcription machinery. CCAR1 also functions as a p53 coactivator and regulates expression of key proliferation-inducing genes [].Cell cycle and apoptosis regulator protein 2 (CCAR2, also known as DBC-1) regulates biological processes such as transcription, heterochromatin formation, metabolism, mRNA splicing, apoptosis, and cell proliferation []. It is a core component of the DBIRD complex, which affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions []. It binds to SIRT1 and is a negative regulator of SIRT1 []. DBC-1 has been implicated in tumorigenesis [].This entry also includes protein SHORT ROOT IN SALT MEDIUM 1 (RSA1, also known as EMB1579) from Arabidopsis. It regulates the transcription of several genes involved in the detoxification of reactive oxygen species generated by salt stress and the SOS1 gene that encodes a plasma membrane Na(+)/H(+) antiporter essential for salt tolerance []. RSA1 is localised to the nucleus and the loss of function of RSA1 affects global transcription and mRNA splicing [].
Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP []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 [, ]. 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 thedissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors [, ].The crystal structure of the GEF region of human Sos1 complexes with Ras has been solved []. 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 [].This entry represents the C-terminal catalytic domain of the Ras guanine-nucleotide exchange factors.
Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyse GTP to GDP []. 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 [, ]. 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 ) and the CDC25 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.The crystal structure of the GEF region of human Sos1 complexes with Ras has been solved []. 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. The signature pattern for this entry spans the helical hairpin.
Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP []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 [, ]. 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 [, ].The crystal structure of the GEF region of human Sos1 complexes with Ras has been solved []. 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 [].This entry represents the catalytic domain of the Ras guanine-nucleotide exchange factors.
