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| Aliases | XPO5, exp5, exportin 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 607845; MGI: 1913789; HomoloGene: 69316; GeneCards: XPO5; OMA:XPO5 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene.[5][6][7] In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme.[8][9][10][11] Once in the cytoplasm, the microRNA (also known as miRNA) can act as a gene silencer by regulating translation of mRNA. Although XPO5 is primarily involved in the transport of pre-miRNA, it has also been reported to transport tRNA.[12]
Much research on XPO5 is ongoing. miRNA is a prominent research topic due to its potential use as a therapeutic, with several miRNA-based drugs already in use.[13]
Mechanism
[edit]Binding to pre-miRNA
[edit]
After RanGTP binds to XPO5, the XPO5-RanGTP complex forms a U-like structure to hold the pre-miRNA. The XPO5-RanGTP complex recognizes pre-miRNA by its two-nucleotide 3’ overhang—a sequence consisting of two bases at the 3’ end of the pre-miRNA that are not paired with other bases. This motif is unique to pre-miRNA, and by recognizing it XPO5 ensures specificity for transporting only pre-miRNA. On its own, pre-miRNA is in a “closed” conformation, with the 3’ overhang flipped up toward the RNA minor groove. However, upon binding to XPO5, the 3’ overhang is flipped downwards away from the rest of the pre-miRNA molecule into an “open” conformation. This helps the backbone phosphates of these two nucleotides form hydrogen bonds with many XPO5 residues, allowing XPO5 to recognize the RNA as pre-miRNA. Because these interactions involve only the RNA phosphate backbone, they are nonspecific and allow XPO5 to recognize and transport any pre-miRNA. The rest of the pre-miRNA stem binds to XPO5 via interactions between the negatively-charged phosphate backbone and several positively-charged interior XPO5 residues.[15]
XPO5 Ternary Complex Transport Mechanism
[edit]The combined structure of XPO5, RanGTP, and pre-miRNA is known as the ternary complex. Once the ternary complex is formed, it diffuses through a nuclear pore complex into the cytoplasm, transporting pre-miRNA into the cytoplasm in the process. Once in the cytoplasm, RanGAP hydrolyzes GTP to GDP, causing a conformational change that releases the pre-miRNA into the cytoplasm.[15]
Export out of the Nucleus
[edit]It has been suggested, through evidence provided by contour maps of water density, that the interior of XPO5 is hydrophilic, while the exterior of XPO5 is hydrophobic.[15] Therefore, this enhances the binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus.[15]
Additional interactions
[edit]Potential oncogenic role
[edit]Recent evidence has shown higher levels of XPO5 in prostate cancer cell lines in-vitro, suggesting that altered XPO5 expression levels may have a role in cancer development. Suppressing XPO5 has also been found to be therapeutic in-vitro.[16] It has also been shown to function as an oncogene in colorectal cancer.[17]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000124571 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000067150 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c Brownawell AM, Macara IG (Jan 2002). "Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins". The Journal of Cell Biology. 156 (1): 53–64. doi:10.1083/jcb.200110082. PMC 2173575. PMID 11777942.
- ^ Bohnsack MT, Regener K, Schwappach B, Saffrich R, Paraskeva E, Hartmann E, Görlich D (Nov 2002). "Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm". The EMBO Journal. 21 (22): 6205–15. doi:10.1093/emboj/cdf613. PMC 137205. PMID 12426392.
- ^ "Entrez Gene: XPO5 exportin 5".
- ^ Yi R, Qin Y, Macara IG, Cullen BR (Dec 2003). "Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs". Genes & Development. 17 (24): 3011–6. doi:10.1101/gad.1158803. PMC 305252. PMID 14681208.
- ^ Wilson RC, Doudna JA (2013). "Molecular mechanisms of RNA interference". Annual Review of Biophysics. 42: 217–39. doi:10.1146/annurev-biophys-083012-130404. PMC 5895182. PMID 23654304.
- ^ Siomi H, Siomi MC (May 2010). "Posttranscriptional regulation of microRNA biogenesis in animals". Molecular Cell. 38 (3): 323–32. doi:10.1016/j.molcel.2010.03.013. PMID 20471939.
- ^ Macias S, Cordiner RA, Cáceres JF (Aug 2013). "Cellular functions of the microprocessor". Biochemical Society Transactions. 41 (4): 838–43. doi:10.1042/BST20130011. hdl:1842/25877. PMID 23863141.
- ^ Gupta, Asmita (2016). "Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t". Biophysical Journal. 110 (6): 1264–1279. Bibcode:2016BpJ...110.1264G. doi:10.1016/j.bpj.2016.02.015. PMC 4816717. PMID 27028637.
- ^ Christopher, Ajay Francis; Kaur, Raman Preet; Kaur, Gunpreet; Kaur, Amandeep; Gupta, Vikas; Bansal, Parveen (2016). "MicroRNA therapeutics: Discovering novel targets and developing specific therapy". Perspectives in Clinical Research. 7 (2): 68–74. doi:10.4103/2229-3485.179431. ISSN 2229-3485. PMC 4840794. PMID 27141472.
- ^ Okada, Chimari; Yamashita, Eiki; Lee, Soo Jae; Shibata, Satoshi; Katahira, Jun; Nakagawa, Atsushi; Yoneda, Yoshihiro; Tsukihara, Tomitake (2009-11-27). "A high-resolution structure of the pre-microRNA nuclear export machinery". Science. 326 (5957): 1275–1279. Bibcode:2009Sci...326.1275O. doi:10.1126/science.1178705. ISSN 1095-9203. PMID 19965479. S2CID 206522317.
- ^ a b c d Wang, Xia (2011). "Dynamic mechanisms for pre-miRNA binding and export by Exportin-5". RNA. 17 (8): 1516–1517. doi:10.1261/rna.2732611. PMC 3153975. PMID 21712399.
- ^ Höti, Naseruddin; Yang, Shuang; Aiyetan, Paul; Kumar, Binod; Hu, Yingwei; Clark, David; Eroglu, Arife Unal; Shah, Punit; Johnson, Tamara (2017-09-04). "Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer". Neoplasia (New York, N.Y.). 19 (10): 817–829. doi:10.1016/j.neo.2017.07.008. ISSN 1522-8002. PMC 5587889. PMID 28881308.
- ^ Shigeyasu, Kunitoshi; Okugawa, Yoshinaga; Toden, Shusuke; Boland, C. Richard; Goel, Ajay (2017-03-01). "Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer". Clinical Cancer Research. 23 (5): 1312–1322. doi:10.1158/1078-0432.CCR-16-1023. ISSN 1557-3265. PMC 5435115. PMID 27553833.
Further reading
[edit]- Calado A, Treichel N, Müller EC, Otto A, Kutay U (Nov 2002). "Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA". The EMBO Journal. 21 (22): 6216–24. doi:10.1093/emboj/cdf620. PMC 137209. PMID 12426393.
- Gwizdek C, Ossareh-Nazari B, Brownawell AM, Doglio A, Bertrand E, Macara IG, Dargemont C (Feb 2003). "Exportin-5 mediates nuclear export of minihelix-containing RNAs". The Journal of Biological Chemistry. 278 (8): 5505–8. doi:10.1074/jbc.C200668200. PMID 12509441.
- Gwizdek C, Ossareh-Nazari B, Brownawell AM, Evers S, Macara IG, Dargemont C (Jan 2004). "Minihelix-containing RNAs mediate exportin-5-dependent nuclear export of the double-stranded RNA-binding protein ILF3". The Journal of Biological Chemistry. 279 (2): 884–91. doi:10.1074/jbc.M306808200. PMID 14570900.
- Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U (Jan 2004). "Nuclear export of microRNA precursors". Science. 303 (5654): 95–8. Bibcode:2004Sci...303...95L. doi:10.1126/science.1090599. PMID 14631048. S2CID 30217099.
- Bohnsack MT, Czaplinski K, Gorlich D (Feb 2004). "Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs". RNA. 10 (2): 185–91. doi:10.1261/rna.5167604. PMC 1370530. PMID 14730017.
- Chen T, Brownawell AM, Macara IG (Aug 2004). "Nucleocytoplasmic shuttling of JAZ, a new cargo protein for exportin-5". Molecular and Cellular Biology. 24 (15): 6608–19. doi:10.1128/MCB.24.15.6608-6619.2004. PMC 444848. PMID 15254228.
- Yi R, Doehle BP, Qin Y, Macara IG, Cullen BR (Feb 2005). "Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs". RNA. 11 (2): 220–6. doi:10.1261/rna.7233305. PMC 1370710. PMID 15613540.