RalGDS belongs to the Ral GDP dissociation stimulator (RalGDS) family []. It has been linked to cancer [].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 [].
RGL3 (RalGDS-like 3) belongs to the Ral GDP dissociation stimulator (RalGDS) family []. RGL3 functions as an exchange factor for Ral and may serve as a downstream effector for both Rit and Ras [, ].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 [].
RGL (RalGDS-like 1) belongs to the Ral GDP dissociation stimulator (RalGDS) family []. It is a binding partner for small G-proteins. The function of RGL1 is not clear.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 signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. Ras is a prolific signalling molecule interacting with a spectrum of effector molecules and acting through more than one signalling pathway. A domain of about 100 residues, termed RA for RalGDS/AF-6 or Ras-Associating, interacts with Ras and other small GTPases. It occurs in one or two copies in a variety of signalling molecules. It can be found associated with many other domains, such as PDZ, Dilute (DIL), GEF, myosin motor, IQ, C1, C2, protein kinase, VPS9 or sterile alpha motif (SAM) [, ].Structurally, the RA domain of RalGDS consists of a five-stranded mixed β-sheet interrupted by a 12 residue α-helix and two additional small α-helices. The structure of the RA domain belongs to the ubiquitin α/β roll superfold and is similar to that of the RBD domain and the N-terminal third of the FERM domain [, ]. The RA domain forms a homodimer where the interdimer surface is composed of two cysteines (Cys 2 in each monomer) forming an intermolecular disulfide bond and two interacting intermolecular antiparallel β-sheets []. The major interaction between Ras and RalGDS RA domain occurs between two antiparallel β-strands: β2 of Ras and β2 of RA. This interaction occurs both at the backbone as well as the side chain level [].
The multi-domain non-structural protein NSP3 is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. While some of the domains differ between CoV genera, eight domains of NSP3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. There are also two transmembrane regions, TM1 and TM2, which exist in all CoVs [].The ubiquitin-like domain 1 (Ubl1) and the Glu-rich acidic region are located at the N-terminal of NSP3. These two regions together are also named "NSP3A". In addition to the four β-strands and two α-helices that are common to ubiquitin-like folds, the globular domain of NSP3A contains two short helices []. NSP3A is well conserved within different SARS-CoV sequencesbut exhibits low sequence identity (less than 35%) to other CoV NSP3 proteins []. It is an essential component of the replication/transcription complex and is involved in multiple biological processes, such as proteolysis and RNA processing [].This entry represents NSP3A that has been shown to bind ssRNA. The overall structure of the SARS-CoV Ubl1 domain is similar to human ubiquitin (Ub) and that of each of the two ubiquitin-like domains of human or mouse interferon-stimulated gene 15 (hISG15 or mISG15). It is also similar to the Ras-interacting domain (RID) of RalGDS [, ].
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 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.
