View source for XPO5

{{Infobox_gene}}
'''Exportin-5''' ('''XPO5''') is a [[protein]] that, in humans, is encoded by the ''XPO5'' [[gene]].<ref name="pmid11777942">{{cite journal | vauthors = Brownawell AM, Macara IG | title = Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins | journal = The Journal of Cell Biology | volume = 156 | issue = 1 | pages = 53–64 | date = Jan 2002 | pmid = 11777942 | pmc = 2173575 | doi = 10.1083/jcb.200110082 }}</ref><ref name="pmid12426392">{{cite journal | vauthors = Bohnsack MT, Regener K, Schwappach B, Saffrich R, Paraskeva E, Hartmann E, Görlich D | title = Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm | journal = The EMBO Journal | volume = 21 | issue = 22 | pages = 6205–15 | date = Nov 2002 | pmid = 12426392 | pmc = 137205 | doi = 10.1093/emboj/cdf613 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: XPO5 exportin 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57510}}</ref> In [[Eukaryote|eukaryotic cells]], the primary purpose of XPO5 is to export [[MicroRNA|pre-microRNA]] (also known as pre-miRNA) out of the [[Cell nucleus|nucleus]] and into the [[cytoplasm]], for further processing by the [[Dicer]] enzyme.<ref name="yi">{{cite journal | vauthors = Yi R, Qin Y, Macara IG, Cullen BR | title = Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs | journal = Genes & Development | volume = 17 | issue = 24 | pages = 3011–6 | date = Dec 2003 | pmid = 14681208 | doi = 10.1101/gad.1158803 | pmc=305252}}</ref><ref name="wilson">{{cite journal | vauthors = Wilson RC, Doudna JA | title = Molecular mechanisms of RNA interference | journal = Annual Review of Biophysics | volume = 42 | pages = 217–39 | date = 2013 | pmid = 23654304 | pmc = 5895182 | doi = 10.1146/annurev-biophys-083012-130404 }}</ref><ref name="siomi">{{cite journal | vauthors = Siomi H, Siomi MC | title = Posttranscriptional regulation of microRNA biogenesis in animals | journal = Molecular Cell | volume = 38 | issue = 3 | pages = 323–32 | date = May 2010 | pmid = 20471939 | doi = 10.1016/j.molcel.2010.03.013 | doi-access = free }}</ref><ref name="macias">{{cite journal | vauthors = Macias S, Cordiner RA, Cáceres JF | title = Cellular functions of the microprocessor | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 838–43 | date = Aug 2013 | pmid = 23863141 | doi = 10.1042/BST20130011 | hdl = 1842/25877 | hdl-access = free }}</ref> Once in the cytoplasm, the microRNA (also known as miRNA) can act as a gene silencer by regulating [[Translation (biology)|translation]] of [[Messenger RNA|mRNA]]. Although XPO5 is primarily involved in the transport of [[MicroRNA|pre-miRNA]], it has also been reported to transport [[tRNA]].<ref>{{Cite journal|last=Gupta|first=Asmita|date=2016|title=Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t|journal=Biophysical Journal|volume=110|issue=6|pages=1264–1279|doi=10.1016/j.bpj.2016.02.015|pmid=27028637|pmc=4816717|bibcode=2016BpJ...110.1264G}}</ref>
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.<ref>{{Cite journal|last1=Christopher|first1=Ajay Francis|last2=Kaur|first2=Raman Preet|last3=Kaur|first3=Gunpreet|last4=Kaur|first4=Amandeep|last5=Gupta|first5=Vikas|last6=Bansal|first6=Parveen|date=2016|title=MicroRNA therapeutics: Discovering novel targets and developing specific therapy|journal=Perspectives in Clinical Research|volume=7|issue=2|pages=68–74|doi=10.4103/2229-3485.179431|issn=2229-3485|pmc=4840794|pmid=27141472 |doi-access=free }}</ref>
== Mechanism ==
=== Binding to pre-miRNA ===
[[File:XPO5 Image.png|thumb|320x320px|Image of XPO5 ternary complex generated in PyMol from crystal structure entry 3A6P in the Protein Data Bank. XPO5 is labeled green, Ran is labeled red, RNA is multi-colored, and GTP is labeled white.<ref name=":1">{{Cite journal|last1=Okada|first1=Chimari|last2=Yamashita|first2=Eiki|last3=Lee|first3=Soo Jae|last4=Shibata|first4=Satoshi|last5=Katahira|first5=Jun|last6=Nakagawa|first6=Atsushi|last7=Yoneda|first7=Yoshihiro|last8=Tsukihara|first8=Tomitake|date=2009-11-27|title=A high-resolution structure of the pre-microRNA nuclear export machinery|journal=Science|volume=326|issue=5957|pages=1275–1279|doi=10.1126/science.1178705|issn=1095-9203|pmid=19965479|bibcode=2009Sci...326.1275O|s2cid=206522317}}</ref>|left]]
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 [[Directionality (molecular biology)|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.<ref name=":0">{{Cite journal|last=Wang|first=Xia|date=2011|title=Dynamic mechanisms for pre-miRNA binding and export by Exportin-5|journal=RNA|volume=17|issue=8|pages=1516–1517|doi=10.1261/rna.2732611|pmid=21712399|pmc=3153975}}</ref>
=== XPO5 Ternary Complex Transport Mechanism ===
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.<ref name=":0" />
=== Export out of the Nucleus ===
It has been suggested, through evidence provided by contour maps of water density, that the interior of XPO5 is [[Hydrophile|hydrophilic]], while the exterior of XPO5 is [[Hydrophobe|hydrophobic]].<ref name=":0" /> Therefore, this enhances the binding capabilities of XPO5 to the nuclear pore complex, allowing for transport of the ternary complex out of the nucleus.<ref name=":0" />
== Additional interactions ==
XPO5 has been shown to [[Protein-protein interaction|interact]] with [[ILF3]]<ref name=pmid11777942 /> and [[Ran (gene)|Ran]].<ref name=pmid11777942/>
== Potential oncogenic role ==
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.<ref>{{Cite journal|last1=Höti|first1=Naseruddin|last2=Yang|first2=Shuang|last3=Aiyetan|first3=Paul|last4=Kumar|first4=Binod|last5=Hu|first5=Yingwei|last6=Clark|first6=David|last7=Eroglu|first7=Arife Unal|last8=Shah|first8=Punit|last9=Johnson|first9=Tamara|date=2017-09-04|title=Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer|journal=Neoplasia (New York, N.Y.)|volume=19|issue=10|pages=817–829|doi=10.1016/j.neo.2017.07.008|issn=1522-8002|pmc=5587889|pmid=28881308}}</ref> It has also been shown to function as an [[oncogene]] in colorectal cancer.<ref>{{Cite journal|last1=Shigeyasu|first1=Kunitoshi|last2=Okugawa|first2=Yoshinaga|last3=Toden|first3=Shusuke|last4=Boland|first4=C. Richard|last5=Goel|first5=Ajay|date=2017-03-01|title=Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer|journal=Clinical Cancer Research|volume=23|issue=5|pages=1312–1322|doi=10.1158/1078-0432.CCR-16-1023|issn=1557-3265|pmc=5435115|pmid=27553833}}</ref>
== References ==
{{reflist|33em}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Calado A, Treichel N, Müller EC, Otto A, Kutay U | title = Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA | journal = The EMBO Journal | volume = 21 | issue = 22 | pages = 6216–24 | date = Nov 2002 | pmid = 12426393 | pmc = 137209 | doi = 10.1093/emboj/cdf620 }}
* {{cite journal | vauthors = Gwizdek C, Ossareh-Nazari B, Brownawell AM, Doglio A, Bertrand E, Macara IG, Dargemont C | title = Exportin-5 mediates nuclear export of minihelix-containing RNAs | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 5505–8 | date = Feb 2003 | pmid = 12509441 | doi = 10.1074/jbc.C200668200 | doi-access = free }}
* {{cite journal | vauthors = Gwizdek C, Ossareh-Nazari B, Brownawell AM, Evers S, Macara IG, Dargemont C | title = Minihelix-containing RNAs mediate exportin-5-dependent nuclear export of the double-stranded RNA-binding protein ILF3 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 2 | pages = 884–91 | date = Jan 2004 | pmid = 14570900 | doi = 10.1074/jbc.M306808200 | doi-access = free }}
* {{cite journal | vauthors = Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U | title = Nuclear export of microRNA precursors | journal = Science | volume = 303 | issue = 5654 | pages = 95–8 | date = Jan 2004 | pmid = 14631048 | doi = 10.1126/science.1090599 | bibcode = 2004Sci...303...95L | s2cid = 30217099 | doi-access = free }}
* {{cite journal | vauthors = Bohnsack MT, Czaplinski K, Gorlich D | title = Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs | journal = RNA | volume = 10 | issue = 2 | pages = 185–91 | date = Feb 2004 | pmid = 14730017 | pmc = 1370530 | doi = 10.1261/rna.5167604 }}
* {{cite journal | vauthors = Chen T, Brownawell AM, Macara IG | title = Nucleocytoplasmic shuttling of JAZ, a new cargo protein for exportin-5 | journal = Molecular and Cellular Biology | volume = 24 | issue = 15 | pages = 6608–19 | date = Aug 2004 | pmid = 15254228 | pmc = 444848 | doi = 10.1128/MCB.24.15.6608-6619.2004 }}
* {{cite journal | vauthors = Yi R, Doehle BP, Qin Y, Macara IG, Cullen BR | title = Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs | journal = RNA | volume = 11 | issue = 2 | pages = 220–6 | date = Feb 2005 | pmid = 15613540 | pmc = 1370710 | doi = 10.1261/rna.7233305 }}
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[[Category:MicroRNA]]