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Exportin-5 (XPO5) is a protein that, in humans, is encoded by the XPO5 gene. In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA out of the nucleus and into the cytoplasm, for further processing by the Dicer enzyme. Once in the cytoplasm, the microRNA 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.[1]
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[2].
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 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.[3]
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.[3]
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. This would enhance binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus.[3]
References
[edit]- ^ Gupta, Asmita (2016). "Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t". BiophysicalJournal. 110: 1264–1279.
- ^ 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.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c Wang, Xia (2011). "Dynamic mechanisms for pre-miRNA binding and export by Exportin-5". RNA. 17: 1516–1517.
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.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - 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.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U (Jan 2004). "Nuclear export of microRNA precursors". Science. 303 (5654): 95–8. doi:10.1126/science.1090599. PMID 14631048.
- 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.