Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This concentration gradient of RanGTP formed across the nucleus helps in the unidirectional trafficking of nuclear proteins.
During nuclear export, RanGTP binds exportin and increases its affinity to bind the cargo. The Ran GTP-cargo-exportin complex transits out of the nucleus through the nuclear pore complex or NPCs. RanBP1 and RanBP2 present near the cytosolic side of the NPCs stimulate RanGAP activity, helping Ran undergo GTP hydrolysis to RanGDP. This weakens the cargo-exportin affinity, eventually leading to cargo release in the cytosol. Unlike RanGTP, RanGDP cannot bind receptors alone and releases the exportins to be recycled back into the nucleus for a second round of cargo export.
The continuous efflux and hydrolysis of RanGTP in the cytosol lowers the RanGTP levels in the nucleus. Nuclear transport factor 2 (NTF2) binds hydrolyzed RanGDP in the cytosol transporting them back to the nucleus to compensate for the loss. Inside the nucleus, RanGDP binds to the Regulators of Chromatin Condensation 1 (RCC1), a RanGEF, and undergoes a GDP/GTP exchange to restore the nuclear RanGTP concentrations.
