Ran (protein)
Ran also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.
Ran is a small G protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein has also been implicated in the control of DNA synthesis and cell cycle progression, as mutations in Ran have been found to disrupt DNA synthesis.
Function
Ran cycle
Ran exists in the cell in two nucleotide-bound forms: GDP-bound and GTP-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor for Ran. RCC1 is also known as RanGEF. Ran's intrinsic GTPase-activity is activated through interaction with Ran GTPase activating protein, facilitated by complex formation with Ran-binding protein. GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle.Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. RCC1 is bound to chromatin and therefore located inside the nucleus. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complex via interaction with the nucleoporin RANBP2. This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein NUTF2, where RCC1 can then catalyze exchange of GDP for GTP on Ran.
Role in nuclear transport during interphase
[Image:RanGTPcycle.png|thumb|left|Ran cycle involvement in nucleocytoplasmic transport at the nuclear pore]Ran is involved in the transport of proteins across the nuclear envelope by interacting with karyopherins and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal are bound by importins and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.