FIGURE 13-36 Mechanism for nuclear import of proteins. In the cytoplasm (top), free importin binds to the NLS of a cargo protein, forming an importin-cargo complex. The importin-cargo complex diffuses through the NPC by transiently interacting with FG-nucleoporins. In the nucleoplasm, Ran·GTP binds to the importin, causing a conformational change that decreases the importin’s affinity for the NLS and releasing the cargo. To support another cycle of import, the importin-Ran·GTP complex is transported back to the cytoplasm. A GTPase-activating protein (GAP) associated with the cytoplasmic filaments of the NPC stimulates Ran to hydrolyze the bound GTP. This generates a conformational change that causes Ran to dissociate from the nuclear transport receptor, which can then initiate another round of import. Ran·GDP is returned to the nucleoplasm, where a guanine nucleotide exchange factor (GEF) causes release of GDP and rebinding of GTP.