Ran (protein)

RAN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1I2M, 1IBR, 1K5D, 1K5G, 1QBK, 1RRP, 2MMC, 2MMG, 3CH5, 3EA5, 3GJ0, 3GJ3, 3GJ4, 3GJ5, 3GJ6, 3GJ7, 3GJ8, 3GJX, 3NBY, 3NBZ, 3NC0, 3NC1, 3ZJY, 4C0Q, 4GMX, 4GPT, 4HAT, 4HAU, 4HAV, 4HAW, 4HAX, 4HAY, 4HAZ, 4HB0, 4HB2, 4HB3, 4HB4, 4OL0, 4WVF, 5CIQ, 5CIT, 5CIW, 5CJ2, 5CLL, 5CLQ, 5DH9, 5DHA, 5DHF, 5DI9, 5DIF, 3A6P, 1A2K, 5DIS, 5BXQ, 5DLQ, 5FYQ, 2N1B, 5JLJ
Identifiers
Aliases	RAN , ARA24, Gsp1, TC4, Ran, member RAS oncogene family
External IDs	OMIM: 601179 MGI: 1333112 HomoloGene: 68143 GeneCards: RAN
Gene location (Human) Chr. Chromosome 12 (human) [1] Band 12q24.33 Start 130,872,037 bp [1] End 130,877,678 bp [1]
Gene location (Mouse) Chr. Chromosome 5 (mouse) [2] Band 5|5 G1.3 Start 129,097,133 bp [2] End 129,101,387 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence stromal cell of endometrium right adrenal gland left adrenal gland rectum anterior pituitary upper lobe of left lung body of stomach left coronary artery prefrontal cortex Top expressed in otic placode yolk sac lens habenula neural tube arcuate nucleus paraventricular nucleus of hypothalamus dorsomedial hypothalamic nucleus supraoptic nucleus ventromedial nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding transcription coactivator activity pre-miRNA binding chromatin binding protein binding androgen receptor binding GTPase activity GTP binding RNA binding cadherin binding magnesium ion binding structural constituent of nuclear pore GDP binding protein heterodimerization activity nuclear export signal receptor activity metal ion binding protein domain specific binding protein-containing complex binding dynein intermediate chain binding importin-alpha family protein binding Cellular component recycling endosome cytosol Flemming body melanosome nucleoplasm midbody RNA nuclear export complex nucleolus centriole chromatin extracellular exosome membrane cytoplasm nucleus extracellular matrix nuclear pore host cell nuclear envelope protein-containing complex male germ cell nucleus manchette sperm flagellum Biological process ribosomal small subunit export from nucleus intracellular transport of virus androgen receptor signaling pathway protein localization to nucleolus mitotic spindle organization DNA metabolic process pre-miRNA export from nucleus cell division positive regulation of transcription, DNA-templated nucleocytoplasmic transport protein export from nucleus protein transport ribosomal large subunit export from nucleus cell cycle positive regulation of protein binding viral process tRNA export from nucleus mitotic cell cycle protein import into nucleus miRNA metabolic process regulation of cholesterol biosynthetic process regulation of gene silencing by miRNA transport mitotic sister chromatid segregation GTP metabolic process snRNA import into nucleus positive regulation of protein import into nucleus spermatid development response to organic cyclic compound hippocampus development actin cytoskeleton organization regulation of protein binding cellular response to mineralocorticoid stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5901 19384 Ensembl ENSG00000132341 ENSMUSG00000029430 UniProt P62826 P62827 RefSeq (mRNA) NM_006325 NM_001300796 NM_001300797 NM_009391 RefSeq (protein) NP_001287725 NP_001287726 NP_006316 NP_033417 Location (UCSC) Chr 12: 130.87 – 130.88 Mb Chr 5: 129.1 – 129.1 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ran (RAs-related Nuclear protein) 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. ^{[5] [6] [7]}

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. ^[8]

Function

Ran cycle

Schematic representation of the 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 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 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 (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 NUTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GDP for GTP on Ran.

Role in nuclear transport during interphase

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 (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 exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.

Role in mitosis

During mitosis, the Ran cycle is involved in mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated. ^{[9] [10]} 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. ^[11] 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 fusion at 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 spinal and bulbar muscular atrophy (Kennedy's disease). 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 spinal and bulbar muscular atrophy. ^{[12] [13]}

Interactions

Ran has been shown to interact with:

• KPNB1, ^{[14] [15] [16]}
• NEK9, ^[17]
• NUTF2, ^{[18] [19]}
• RANBP1, ^{[14] [20] [21]}
• RANGAP1, ^{[22] [23] [24]}
• RCC1, ^{[20] [21] [25] [26]}
• TNPO1, ^{[27] [28]}
• TNPO2, ^[28]
• XPO1, ^{[14] [29] [30]} and
• XPO5. ^[31]

Regulation

The expression of Ran is repressed by the microRNA miR-10a. ^[32]

See also

• GTPase
• importin
• mitosis
• nuclear envelope
• nuclear transport
• RGPD5
• small GTPase

References

1. GRCh38: Ensembl release 89: ENSG00000132341 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029430 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Moore MS, Blobel G (May 1994). "A G protein involved in nucleocytoplasmic transport: the role of Ran". Trends Biochem. Sci. 19 (5): 211–6. doi:10.1016/0968-0004(94)90024-8. PMID   7519373.
6. Avis JM, Clarke PR (October 1996). "Ran, a GTPase involved in nuclear processes: its regulators and effectors". J. Cell Sci. 109 (10): 2423–7. doi:10.1242/jcs.109.10.2423. PMID   8923203.
7. Dasso M, Pu RT (August 1998). "Nuclear transport: run by Ran?". Am. J. Hum. Genet. 63 (2): 311–6. doi:10.1086/301990. PMC   1377330 . PMID   9683621.
8. Sazer S, Dasso M (April 2000). "The ran decathlon: multiple roles of Ran". J. Cell Sci. 113 (7): 1111–8. doi:10.1242/jcs.113.7.1111. PMID   10704362.
9. Gruss OJ, Vernos I (September 2004). "The mechanism of spindle assembly: functions of Ran and its target TPX2". J. Cell Biol. 166 (7): 949–55. doi:10.1083/jcb.200312112. PMC   2172015 . PMID   15452138.
10. Ciciarello M, Mangiacasale R, Lavia P (August 2007). "Spatial control of mitosis by the GTPase Ran". Cell. Mol. Life Sci. 64 (15): 1891–914. doi:10.1007/s00018-007-6568-2. PMID   17483873. S2CID   8687055.
11. Carazo-Salas RE, Guarguaglini G, Gruss OJ, Segref A, Karsenti E, Mattaj IW (July 1999). "Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation". Nature. 400 (6740): 178–81. Bibcode:1999Natur.400..178C. doi:10.1038/22133. PMID   10408446. S2CID   4417176.
12. Hsiao PW, Lin DL, Nakao R, Chang C (July 1999). "The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator". J. Biol. Chem. 274 (29): 20229–34. doi: 10.1074/jbc.274.29.20229 . PMID   10400640.
13. Sampson ER, Yeh SY, Chang HC, Tsai MY, Wang X, Ting HJ, Chang C (2001). "Identification and characterization of androgen receptor associated coregulators in prostate cancer cells". J. Biol. Regul. Homeost. Agents. 15 (2): 123–9. PMID   11501969.
14. Plafker K, Macara IG (2000). "Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1". Mol. Cell. Biol. 20 (10): 3510–21. doi:10.1128/MCB.20.10.3510-3521.2000. PMC   85643 . PMID   10779340.
15. Kutay U, Izaurralde E, Bischoff FR, Mattaj IW, Görlich D (1997). "Dominant-negative mutants of importin-beta block multiple pathways of import and export through the nuclear pore complex". EMBO J. 16 (6): 1153–63. doi:10.1093/emboj/16.6.1153. PMC   1169714 . PMID   9135132.
16. Percipalle P, Clarkson WD, Kent HM, Rhodes D, Stewart M (1997). "Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import". J. Mol. Biol. 266 (4): 722–32. doi:10.1006/jmbi.1996.0801. PMID   9102465.
17. Roig J, Mikhailov A, Belham C, Avruch J (2002). "Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression". Genes Dev. 16 (13): 1640–58. doi:10.1101/gad.972202. PMC   186374 . PMID   12101123.
18. Cushman I, Bowman BR, Sowa ME, Lichtarge O, Quiocho FA, Moore MS (2004). "Computational and biochemical identification of a nuclear pore complex binding site on the nuclear transport carrier NTF2". J. Mol. Biol. 344 (2): 303–10. doi:10.1016/j.jmb.2004.09.043. PMID   15522285.
19. Stewart M, Kent HM, McCoy AJ (1998). "Structural basis for molecular recognition between nuclear transport factor 2 (NTF2) and the GDP-bound form of the Ras-family GTPase Ran". J. Mol. Biol. 277 (3): 635–46. doi:10.1006/jmbi.1997.1602. PMID   9533885.
20. Steggerda SM, Paschal BM (2000). "The mammalian Mog1 protein is a guanine nucleotide release factor for Ran". J. Biol. Chem. 275 (30): 23175–80. doi: 10.1074/jbc.C000252200 . PMID   10811801.
21. Ren M, Villamarin A, Shih A, Coutavas E, Moore MS, LoCurcio M, Clarke V, Oppenheim JD, D'Eustachio P, Rush MG (1995). "Separate domains of the Ran GTPase interact with different factors to regulate nuclear protein import and RNA processing". Mol. Cell. Biol. 15 (4): 2117–24. doi:10.1128/MCB.15.4.2117. PMC   230439 . PMID   7891706.
22. Hillig RC, Renault L, Vetter IR, Drell T, Wittinghofer A, Becker J (1999). "The crystal structure of rna1p: a new fold for a GTPase-activating protein". Mol. Cell. 3 (6): 781–91. doi: 10.1016/S1097-2765(01)80010-1 . PMID   10394366.
23. Becker J, Melchior F, Gerke V, Bischoff FR, Ponstingl H, Wittinghofer A (1995). "RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae". J. Biol. Chem. 270 (20): 11860–5. doi: 10.1074/jbc.270.20.11860 . PMID   7744835.
24. Bischoff FR, Klebe C, Kretschmer J, Wittinghofer A, Ponstingl H (1994). "RanGAP1 induces GTPase activity of nuclear Ras-related Ran". Proc. Natl. Acad. Sci. U.S.A. 91 (7): 2587–91. Bibcode:1994PNAS...91.2587B. doi: 10.1073/pnas.91.7.2587 . PMC   43414 . PMID   8146159.
25. Renault L, Kuhlmann J, Henkel A, Wittinghofer A (2001). "Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1)". Cell. 105 (2): 245–55. doi: 10.1016/S0092-8674(01)00315-4 . PMID   11336674. S2CID   12827419.
26. Azuma Y, Renault L, García-Ranea JA, Valencia A, Nishimoto T, Wittinghofer A (1999). "Model of the ran-RCC1 interaction using biochemical and docking experiments". J. Mol. Biol. 289 (4): 1119–30. doi:10.1006/jmbi.1999.2820. PMID   10369786.
27. Chook YM, Blobel G (1999). "Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp". Nature. 399 (6733): 230–7. Bibcode:1999Natur.399..230C. doi:10.1038/20375. PMID   10353245. S2CID   4413233.
28. Shamsher MK, Ploski J, Radu A (2002). "Karyopherin beta 2B participates in mRNA export from the nucleus". Proc. Natl. Acad. Sci. U.S.A. 99 (22): 14195–9. Bibcode:2002PNAS...9914195S. doi: 10.1073/pnas.212518199 . PMC   137860 . PMID   12384575.
29. Tickenbrock L, Cramer J, Vetter IR, Muller O (2002). "The coiled coil region (amino acids 129-250) of the tumor suppressor protein adenomatous polyposis coli (APC). Its structure and its interaction with chromosome maintenance region 1 (Crm-1)". J. Biol. Chem. 277 (35): 32332–8. doi: 10.1074/jbc.M203990200 . PMID   12070164.
30. Fornerod M, Ohno M, Yoshida M, Mattaj IW (1997). "CRM1 is an export receptor for leucine-rich nuclear export signals". Cell. 90 (6): 1051–60. doi: 10.1016/S0092-8674(00)80371-2 . PMID   9323133. S2CID   15119502.
31. Brownawell AM, Macara IG (2002). "Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins". J. Cell Biol. 156 (1): 53–64. doi:10.1083/jcb.200110082. PMC   2173575 . PMID   11777942.
32. Ørom UA, Nielsen FC, Lund AH (2008). "MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation". Mol Cell. 30 (4): 460–71. doi: 10.1016/j.molcel.2008.05.001 . PMID   18498749.

External links

• ran+GTP-Binding+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Patel SS. "Animations of nuclear transport factors, including Ran (1 of 2 pages)". Nuclear Transport Animations. Archived from the original on 2009-02-07. Retrieved 2008-06-12.
• Patel SS. "Animations of nuclear transport factors, including Ran (2 of 2 pages)". Nuclear Transport Animations. Archived from the original on 2009-02-07. Retrieved 2008-06-12.