Ral GTPase-activating protein subunit beta (RALGAPB) is a non-catalytic subunit of the heterodimeric RalGAP1 and RalGAP2 complexes which act as GTPase activators for the Ras-like small GTPases RALA and RALB [].
Ral protein family, including RALA and RALB, belongs to the RAS family of small GTPases. Like other RAS GTPases, Ral proteins function as molecular switches alternating between inactive GDP-bound and active GT-bound states [].In humans, RALA and RALB are activated in tumour-derived cell lines. RALA severely impairs the anchorage-independent proliferation of cancer cell lines [], while RALB is required to suppress apoptotic checkpoint activation and is essential for the survival of a variety of tumour-derived cell lines []. RALA and RALB share the same effector molecules, such as SEC5 and EXO84. However, they seem to function in distinct but inter-related biological processes. RALA regulates the assembly interface of a full octameric exocyst complex through interaction with Sec5 and Exo84 []. The RALB/Sec5 effector complex is involved in the TBK1-dependent innate immune signaling [], while the interaction between PALB and EXO84 promotes the assembly of catalytically active ULK1 and the beclin-1-VPS34 autophagy initiation complex []. This entry also includes Xenopus RalA and RalB. RalB regulates the actin cytoskeleton during the early development and affects gastrulation [].
RalR was originally thought to inhibit restriction modification []but instead is part of a toxin/antitoxin system and functions as a non-specific DNase []. Toxin RalR functions as a non-specific endonuclease that cleaves methylated and unmethylated DNA. The adjacent gene product, RalA (for RalR antitoxin), functions as an antitoxin for RalR.
This entry includes RalGPS1 (also known as RalGEF2) and RalGPS2. RalGPS1 and RalGPS2 are guanine nucleotide exchange factors for Ral (RalA and RalB), a ubiquitously expressed Ras-like small GTPase [, ]. The PH-PxxP domain of RalGPS2 acts as a negative regulator for RalA GTPase activation and promotes PC12 cellsdifferentiation [].
The activity of GTPases is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Tuberin (tuberous sclerosis 2 protein or Tsc2) is believed to be a tumor suppressor and is able to stimulate specific GTPases. It stimulates the intrinsic GTPase activity of the Ras-related protein Rap1A and Rab5 [, ]. In complex with Tsc1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. It acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 [, ]. Ral GTPase-activating protein subunit alpha is the catalytic subunit of the heterodimeric RalGAP complex which acts as a GTPase activator for the Ras-like small GTPases RalA and RalB []. RalGAP complexes share structural and catalytic similarities with the tuberous sclerosis tumor suppressor complex [].
RGL2 (RalGDS-like 2) belongs to the Ral GDP dissociation stimulator (RalGDS) family []. The C-terminal fragment (Ras/Rap-binding domain) of RGL2 interacts specifically with Ras family proteins that share identical effector domain sequences with Rap1 (H-Ras, R-Ras, Tc21). The binding ability of RGL2 to H-Ras can be regulated through a PKA phosphorylation site identified in this C-terminal domain []. This phoshorylation site is only conserved in the RGL2 murine orthologue, Rlf, but not in RalGDS, RGL and RGL3 []. RGL2 is a guanine nucleotide exchange factor (GEF) for RalA, which plays an important role in the assembly of the exocyst complex. R-Ras regulates exocytosis by RGL2/Rlf-mediated activation of RalA on endosomes [].RalGDS family members can act both as Ras effectors and as guanine nucleotide exchange factors (GEFs) for Ral. They act downstream of Ras and bind to the GTP-bound active form of Ras or Ras family members. They also promote the GDP to GTP exchange for Ral small GTPase, member of the Ras family []. Due to their double action, the RalGDS proteins bridge Ras and Ral [].
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 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.
