- Ran (biology)
GTPaseis a small GTPasethat is involved in transport into and out of the cell nucleusduring interphaseand also involved in mitosis. It is a member of the Rassuperfamily of GTPases.cite journal | author = Moore MS, Blobel G | title = A G protein involved in nucleocytoplasmic transport: the role of Ran | journal = Trends Biochem. Sci. | volume = 19 | issue = 5 | pages = 211–6 | year = 1994 | month = May | pmid = 7519373 | doi = | url = | issn = ] cite journal | author = Avis JM, Clarke PR | title = Ran, a GTPase involved in nuclear processes: its regulators and effectors | journal = J. Cell. Sci. | volume = 109 ( Pt 10) | issue = | pages = 2423–7 | year = 1996 | month = October | pmid = 8923203 | doi = | url = http://jcs.biologists.org/cgi/content/abstract/109/10/2423 | issn = ] cite journal | author = Dasso M, Pu RT | title = Nuclear transport: run by Ran? | journal = Am. J. Hum. Genet. | volume = 63 | issue = 2 | pages = 311–6 | year = 1998 | month = August | pmid = 9683621 | pmc = 1377330 | doi = 10.1086/301990 | url = | issn = ]
Ran (RAs-related Nuclear protein) is a small GTP binding protein belonging to the RAS superfamily that is essential for the translocation of RNA and proteins through the nuclear pore complex. The RAN protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of RAN requires the presence of regulator of chromosome condensation 1 (RCC1). Mutations in RAN disrupt DNA synthesis. Because of its many functions, it is likely that RAN interacts with several other proteins.cite journal | author = Sazer S, Dasso M | title = The ran decathlon: multiple roles of Ran | journal = J. Cell. Sci. | volume = 113 ( Pt 7) | issue = | pages = 1111–8 | year = 2000 | month = April | pmid = 10704362 | doi = | url = http://jcs.biologists.org/cgi/content/abstract/113/7/1111 | issn = ]
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 factorfor Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase-activity is activated through interaction with Ran GTPase activating protein(RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). 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
chromatinand therefore located inside the nucleus. RanGAP is cytoplasmicin yeast and bound to the nuclear envelopein plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complexvia interaction with the nucleoporinRanBP2 (Nup358). 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 NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GTP for GDP on Ran.
nuclear transportduring interphase
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(NLS) 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 exportinin a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.
During mitosis, the Ran cycle is involved in
mitotic spindleassembly and nuclear envelope reassembly after the chromosomes have been separated.cite journal | author = Gruss OJ, Vernos I | title = The mechanism of spindle assembly: functions of Ran and its target TPX2 | journal = J. Cell Biol. | volume = 166 | issue = 7 | pages = 949–55 | year = 2004 | month = September | pmid = 15452138 | pmc = 2172015 | doi = 10.1083/jcb.200312112 | url = | issn = ] cite journal | author = Ciciarello M, Mangiacasale R, Lavia P | title = Spatial control of mitosis by the GTPase Ran | journal = Cell. Mol. Life Sci. | volume = 64 | issue = 15 | pages = 1891–914 | year = 2007 | month = August | pmid = 17483873 | doi = 10.1007/s00018-007-6568-2 | url = | issn = ] During prophase, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the chromosomes as RCC1, a nucleotide exchange factor, stays attached to chromatin. RanBP2 (Nup358) and RanGAP move to the kinetochores where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle. In telophase, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusionat the reforming nuclear envelopes of the daughter nuclei.
Ran and the androgen receptor
RAN is an
androgen receptor(AR) coactivator (ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of Kennedy's disease.cite journal | author = Hsiao PW, Lin DL, Nakao R, Chang C | title = The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator | journal = J. Biol. Chem. | volume = 274 | issue = 29 | pages = 20229–34 | year = 1999 | month = July | pmid = 10400640 | doi = 10.1074/jbc.274.29.20229 | url = | issn = ] cite journal | author = Sampson ER, Yeh SY, Chang HC, Tsai MY, Wang X, Ting HJ, Chang C | title = Identification and characterization of androgen receptor associated coregulators in prostate cancer cells | journal = J. Biol. Regul. Homeost. Agents | volume = 15 | issue = 2 | pages = 123–9 | year = 2001 | pmid = 11501969 | doi = | url = | issn = ]
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