RANRan (Ras-related nuclear proteins) /TC4 subfamily of small GTPases
|SMART accession number:||SM00176|
|Description:||Ran is involved in the active transport of proteins through nuclear pores.|
|Interpro abstract (IPR002041):|
Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain [(PUBMED:2122258)], [(PUBMED:1898771)]. Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity [(PUBMED:2029511)].
Crystallographic analysis of various small G proteins revealed the presence of a 20 kDa catalytic domain that is unique for the whole superfamily [(PUBMED:1898771)], [(PUBMED:2196171)]. The domain is built of five alpha helices (A1-A5), six beta-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound form, allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg(2+) and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg(2+) binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base [(PUBMED:11995995)].
The small GTPase superfamily can be divided in 8 different families:
Ran (or TC4), is an evolutionary conserved member of the Ras superfamily of small GTPases that regulates all receptor-mediated transport between the nucleus and the cytoplasm. Ran has been implicated in a large number of processes, including nucleocytoplasmic transport, RNA synthesis, processing and export and cell cycle checkpoint control [(PUBMED:7885480), (PUBMED:8851043)]. Ran plays a crucial role in both import/export pathways and determines the directionality of nuclear transport. Import receptors (importins) bind their cargos in the cytoplasm where the concentration of RanGTP is low (due to action of RanGAP), and release their cargos in the nucleus where the concentration of RanGTP is high (due to action of RanGEF) [(PUBMED:12019565), (PUBMED:17170104)]. Export receptors (exportins) respond to RanGTP in the opposite manner. Furthermore, it has been shown that nuclear transport factor 2 (NTF2, IPR002075) stimulates efficient nuclear import of a cargo protein. NTF2 binds specifically to RanGDP and to the FXFG repeat containing nucleoporins [(PUBMED:10698256)].
Ran is generally included in the RAS 'superfamily' of small GTP-binding proteins [(PUBMED:2029511)], but it is only slightly related to the other RAS proteins. It also differs from RAS proteins in that it lacks cysteine residues at its C-terminal and is therefore not subject to prenylation. Instead, Ran has an acidic C terminus. It is, however, similar to RAS family members in requiring a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity.
Ran consists of a core domain that is structurally similar to the GTP-binding domains of other small GTPases but, in addition, Ran has a C-terminal extension consisting of an unstructured linker and a 16 residue alpha-helix that is located opposite the "Switch I" region in the RanGDP structure [(PUBMED:12051861)]. Three regions of Ran change conformation depending on the nucleotide bound, the Switch I and II regions, which interact with the bound nucleotide, as well as the C-terminal extension. In RanGDP, the C-terminal extension contacts the core of the protein, while in RanGTP, the extension is extending away from the core, most likely due to a steric clash between the switch I region and the linker part of the C-terminal extension. This suggests that the C-terminal extension in RanGDP is crucial for shielding residues in the core domain and preventing the switch regions from adopting a GTP-like form. This prevents binding of transport factors to RanGDP that would otherwise lead to uncoordinated interaction between importin beta-like proteins and cellular factors.
|GO process:||intracellular protein transport (GO:0006886), signal transduction (GO:0007165), nucleocytoplasmic transport (GO:0006913)|
|GO function:||GTP binding (GO:0005525), GTPase activity (GO:0003924)|
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