ABSTRACT
Ran, a member of the Ras superfamily of small GTPases, is highly conserved in all eukaryotic cells from the ‘primitive’ Giardia lamblia to yeasts, plants and animals. The biological activity of Ran is determined both by its localization and its guaninenucleotide bound state (Clarke and Zhang, 2001). During interphase, Ran is concentrated in the nucleus by an active import mechanism involving NTF-2. Like other GTPases, Ran exists in GTP-and GDP-bound states that interact differently with its regulators and effectors (Kunzler and Hurt, 2001). The intrinsic GTPase activity of Ran is very low, but it is greatly stimulated by the interaction of a GTPase-activating protein (RanGAP1) located at the cytoplasmic face of the nuclear pore and in the cytoplasm. Ran GTPase activity is further stimulated by interaction with the Ran-GTP binding domains of Ran binding protein 1 (RanBP1), a mobile but predominantly cytoplasmic protein, and Ran binding protein 2 (RanBP2/Nup358), a component of the cytoplasmic filaments of the nuclear pore complex (NPC). These activities ensure that the relatively low concentration of Ran in the cytoplasm is converted to the GDP-bound state. By contrast, a high concentration of Ran-GTP is generated in the nucleus by RCC1 (Kalab et al., 2002). Generation of Ran-GTP in the nucleus may also be promoted by the nucleotidedestabilizing factor Mog1, which may act together with Ran-GTP binding proteins to dissociate GDP from Ran and reloading with GTP (Nicolás et al., 2001).
