In the case of nuclear pore transport, the GEFs that operate on Ran are found in the nucleus, while Ran GAPs are cytosolic (Fig. 10.4). Thus nucleoplasmic Ran is predominantly in the GTP bound state (Ran:GTP), while most cytosolic Ran has GDP bound (Ran:GDP).
Figure 10.5 shows how Ran regulates import of proteins into the nucleus. An import transporter binds the nuclear localization sequence on the protein. As long as the transporter remains on the cytosolic side of the nuclear envelope, its cargo will remain bound. However,
once the transporter finds itself on the nucleoplasmic side, Ran in its active, GTP-bound state binds and causes the cargo to be released. Now, as long as the transporter remains on the nucleoplasmic side, it will have Ran:GTP bound and will be unable to bind cargo. However, once the transporter finds itself on the cytoplasmic side Ran-GAPs attached to the cytosolic face of the nuclear pore complex will cause Ran to hydrolyze its bound GTP to GDP and Ran will dissociate from the transporter, which is then able to bind more cargo.
The same principle is used when a protein is to be exported from the nucleus (Fig. 10.6). In this case the export receptor can only bind proteins with an export sequence if they also bind Ran:GTP. As long as the transporter remains on the nucleoplasmic side of the nuclear envelope, its cargo will remain bound. However, once the transporter finds itself on the cytoplasmic side Ran GAPs will cause Ran to hydrolyze its bound GTP to GDP and both Ran and the cargo will dissociate from the transporter, which is then unable to bind more cargo until it moves back into the nucleoplasm where Ran:GTP is available.
Although Ran can drive both nuclear import and nuclear export, in each case it is the active GTP-bound form of the protein that binds to the transporter. The GDP-bound form is inactive and cannot bind the transporter.
Some proteins move back and forth between the cytosol and the nucleus by successively revealing and masking nuclear localization sequences. For example, the glucocorti-coid receptor (page 121) only reveals its nuclear localization sequence when it has bound glucocorticoid.
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