XPO1 explained

Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs.

History

XPO1 (CRM1) originally was identified in the fission yeast Schizosaccharomyces pombe in a genetic screen, and investigators determined that it was involved in control of the chromosome structure.[1] It was later shown to be the nuclear transport receptor for cargos with leucine-rich nuclear export signals (NES).[2] [3] [4] [5] The structural details of the interaction of XPO1 with its cargos were revealed two decades after the gene was identified.[6] [7] [8] [9]

Function

XPO1 mediates NES-dependent protein transport. It exports several hundreds of different proteins from the nucleus.[10] [11] XPO1 is involved in the nuclear export of ribosomal subunits.[12] [13] [14] XPO1 plays a role in export of various RNAs including U snRNAs, rRNAs (as a part of ribosomal subunits), and some mRNAs.[15] [16] [17]

Medical relevance

XPO1 is involved in various viral infections. For example, it is required for the nuclear export of HIV-1 RNA in complex with the viral protein Rev, an event that is a crucial part of the infection cycle.[18] XPO1 is affected in some cancer types [19] and is therefore viewed as a target for development of anti-cancer drugs.[20] Selinexor, a drug specifically targeting XPO1, was approved by the FDA for treatment of multiple myeloma.[21]

Interactions

XPO1 has been shown to interact with:

See also

Further reading

External links

Notes and References

  1. Adachi. Y.. Yanagida. M.. 1989-04-01. Higher order chromosome structure is affected by cold-sensitive mutations in a Schizosaccharomyces pombe gene crm1+ which encodes a 115-kD protein preferentially localized in the nucleus and its periphery.. Journal of Cell Biology. en. 108. 4. 1195–1207. 2115495. 10.1083/jcb.108.4.1195. 2647765 . 0021-9525. free.
  2. Fornerod. M.. Ohno. M.. Yoshida. M.. Mattaj. I. W.. 1997-09-19. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 90. 6. 1051–1060. 10.1016/s0092-8674(00)80371-2. 0092-8674. 9323133. free.
  3. Fukuda. M.. Asano. S.. Nakamura. T.. Adachi. M.. Yoshida. M.. Yanagida. M.. Nishida. E.. 1997-11-20. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 390. 6657. 308–311. 10.1038/36894. 0028-0836. 9384386. 1997Natur.390..308F . 4420607 .
  4. Stade. K.. Ford. C. S.. Guthrie. C.. Weis. K.. 1997-09-19. Exportin 1 (Crm1p) is an essential nuclear export factor. Cell. 90. 6. 1041–1050. 10.1016/s0092-8674(00)80370-0. 0092-8674. 9323132. free.
  5. Ossareh-Nazari. B.. Bachelerie. F.. Dargemont. C.. 1997-10-03. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 278. 5335. 141–144. 10.1126/science.278.5335.141. 0036-8075. 9311922.
  6. Monecke. Thomas. Güttler. Thomas. Neumann. Piotr. Dickmanns. Achim. Görlich. Dirk. Ficner. Ralf. 2009-05-22. Crystal structure of the nuclear export receptor CRM1 in complex with Snurportin1 and RanGTP. Science. 324. 5930. 1087–1091. 10.1126/science.1173388. 1095-9203. 19389996. 2009Sci...324.1087M . 21116091 . free.
  7. Dong. Xiuhua. Biswas. Anindita. Süel. Katherine E.. Jackson. Laurie K.. Martinez. Rita. Gu. Hongmei. Chook. Yuh Min. 2009-04-30. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature. 458. 7242. 1136–1141. 10.1038/nature07975. 1476-4687. 3437623. 19339969. 2009Natur.458.1136D .
  8. Dong. Xiuhua. Biswas. Anindita. Chook. Yuh Min. May 2009. Structural basis for assembly and disassembly of the CRM1 nuclear export complex. Nature Structural & Molecular Biology. 16. 5. 558–560. 10.1038/nsmb.1586. 1545-9985. 3437629. 19339972.
  9. Güttler. Thomas. Madl. Tobias. Neumann. Piotr. Deichsel. Danilo. Corsini. Lorenzo. Monecke. Thomas. Ficner. Ralf. Sattler. Michael. Görlich. Dirk. November 2010. NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. Nature Structural & Molecular Biology. 17. 11. 1367–1376. 10.1038/nsmb.1931. 1545-9985. 20972448. 11858/00-001M-0000-0012-D4DB-B. 21593381 . free.
  10. Thakar. Ketan. Karaca. Samir. Port. Sarah A.. Urlaub. Henning. Kehlenbach. Ralph H.. March 2013. Identification of CRM1-dependent Nuclear Export Cargos Using Quantitative Mass Spectrometry. Molecular & Cellular Proteomics . 12. 3. 664–678. 10.1074/mcp.M112.024877. 1535-9484. 3591659. 23242554 . free .
  11. Kırlı. Koray. Karaca. Samir. Dehne. Heinz Jürgen. Samwer. Matthias. Pan. Kuan Ting. Lenz. Christof. Urlaub. Henning. Görlich. Dirk. 2015-12-17. A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife. 4. 10.7554/eLife.11466. 2050-084X. 4764573. 26673895 . free .
  12. Moy. T. I.. Silver. P. A.. 1999-08-15. Nuclear export of the small ribosomal subunit requires the ran-GTPase cycle and certain nucleoporins. Genes & Development. 13. 16. 2118–2133. 10.1101/gad.13.16.2118. 0890-9369. 316945. 10465789.
  13. Ho. J. H.. Kallstrom. G.. Johnson. A. W.. 2000-11-27. Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit. The Journal of Cell Biology. 151. 5. 1057–1066. 10.1083/jcb.151.5.1057. 0021-9525. 2174350. 11086007.
  14. Zemp. Ivo. Wild. Thomas. O'Donohue. Marie-Françoise. Wandrey. Franziska. Widmann. Barbara. Gleizes. Pierre-Emmanuel. Kutay. Ulrike. 2009-06-29. Distinct cytoplasmic maturation steps of 40S ribosomal subunit precursors require hRio2. The Journal of Cell Biology. 185. 7. 1167–1180. 10.1083/jcb.200904048. 1540-8140. 2712965. 19564402.
  15. Cullen. B. R.. June 2000. Nuclear RNA export pathways. Molecular and Cellular Biology. 20. 12. 4181–4187. 10.1128/mcb.20.12.4181-4187.2000. 0270-7306. 85787. 10825183.
  16. Köhler. Alwin. Hurt. Ed. October 2007. Exporting RNA from the nucleus to the cytoplasm. Nature Reviews Molecular Cell Biology. en. 8. 10. 761–773. 10.1038/nrm2255. 17786152 . 10836137 . 1471-0080.
  17. 2016-05-22. Nucleocytoplasmic Transport of RNAs and RNA–Protein Complexes. Journal of Molecular Biology. en. 428. 10. 2040–2059. 10.1016/j.jmb.2015.09.023. 0022-2836. free. Sloan . Katherine E. . Gleizes . Pierre-Emmanuel . Bohnsack . Markus T. . 26434509 .
  18. Booth. David S. Cheng. Yifan. Frankel. Alan D. 2014-12-08. Sundquist. Wesley I. The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA. eLife. 3. e04121. 25486595 . 10.7554/eLife.04121. 4360530 . 2050-084X. free.
  19. Taylor. Justin. Sendino. Maria. Gorelick. Alexander N.. Pastore. Alessandro. Chang. Matthew T.. Penson. Alexander V.. Gavrila. Elena I.. Stewart. Connor. Melnik. Ella M.. Herrejon Chavez. Florisela. Bitner. Lillian. October 2019. Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis. Cancer Discovery. 9. 10. 1452–1467. 10.1158/2159-8290.CD-19-0298. 2159-8290. 6774834. 31285298.
  20. Fung. Ho Yee Joyce. Chook. Yuh Min. August 2014. Atomic basis of CRM1-cargo recognition, release and inhibition. Seminars in Cancer Biology. 27. 52–61. 10.1016/j.semcancer.2014.03.002. 1096-3650. 4108548. 24631835.
  21. Research. Center for Drug Evaluation and. 2019-12-20. FDA grants accelerated approval to selinexor for multiple myeloma. FDA. en.
  22. Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI . Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export . J. Biol. Chem. . 277 . 17 . 14355–8 . April 2002 . 11889117 . 10.1074/jbc.C100762200 . free .
  23. Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM . CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis . Mol. Biol. Cell . 14 . 1 . 201–13 . January 2003 . 12529437 . 140238 . 10.1091/mbc.E02-06-0319 .
  24. Raval A, Weissman JD, Howcroft TK, Singer DS . The GTP-binding domain of class II transactivator regulates its nuclear export . J. Immunol. . 170 . 2 . 922–30 . January 2003 . 12517958 . 10.4049/jimmunol.170.2.922. free .
  25. Voong LN, Slater AR, Kratovac S, Cressman DE . Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator . J. Biol. Chem. . 283 . 14 . 9031–9 . April 2008 . 18245089 . 2431044 . 10.1074/jbc.M706487200 . free .
  26. Thomas F, Kutay U . Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway . J. Cell Sci. . 116 . Pt 12 . 2409–19 . June 2003 . 12724356 . 10.1242/jcs.00464 . free .
  27. Kehlenbach RH, Dickmanns A, Kehlenbach A, Guan T, Gerace L . A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export . J. Cell Biol. . 145 . 4 . 645–57 . May 1999 . 10330396 . 2133185 . 10.1083/jcb.145.4.645.
  28. Singh BB, Patel HH, Roepman R, Schick D, Ferreira PA . The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1 . J. Biol. Chem. . 274 . 52 . 37370–8 . Dec 1999 . 10601307 . 10.1074/jbc.274.52.37370. free . 2066/120791 . free .
  29. Lindsay ME, Holaska JM, Welch K, Paschal BM, Macara IG . Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export . J. Cell Biol. . 153 . 7 . 1391–402 . June 2001 . 11425870 . 2150735 . 10.1083/jcb.153.7.1391.
  30. Lindsay ME, Plafker K, Smith AE, Clurman BE, Macara IG . Npap60/Nup50 is a tri-stable switch that stimulates importin-alpha:beta-mediated nuclear protein import . Cell . 110 . 3 . 349–60 . August 2002 . 12176322 . 10.1016/s0092-8674(02)00836-x. 15515037 . free .
  31. Tickenbrock L, Cramer J, Vetter IR, Muller O . 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 . August 2002 . 12070164 . 10.1074/jbc.M203990200 . free .
  32. Plafker K, Macara IG . Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1 . Mol. Cell. Biol. . 20 . 10 . 3510–21 . May 2000 . 10779340 . 85643 . 10.1128/mcb.20.10.3510-3521.2000.
  33. Fornerod M, Ohno M, Yoshida M, Mattaj IW . CRM1 is an export receptor for leucine-rich nuclear export signals . Cell . 90 . 6 . 1051–60 . September 1997 . 9323133 . 10.1016/s0092-8674(00)80371-2. 15119502 . free .
  34. Craig E, Zhang ZK, Davies KP, Kalpana GV . A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis . EMBO J. . 21 . 1–2 . 31–42 . January 2002 . 11782423 . 125819 . 10.1093/emboj/21.1.31 .
  35. Kanai M, Hanashiro K, Kim SH, Hanai S, Boulares AH, Miwa M, Fukasawa K . Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation . Nat. Cell Biol. . 9 . 10 . 1175–83 . September 2007 . 17891139 . 10.1038/ncb1638 . 13433567 .
  36. Shao C, Lu C, Chen L, Koty PP, Cobos E, Gao W . p53-Dependent anticancer effects of leptomycin B on lung adenocarcinoma . Cancer Chemother. Pharmacol. . 67 . 6 . 1369–80 . August 2010 . 20803015 . 10.1007/s00280-010-1434-6 . 27127578 .

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