XPO1

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.

XPO1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1W9C, 2L1L, 3GB8, 4BSM, 4BSN, 5DIS
Identifiers
Aliases	XPO1, CRM1, emb, exp1, exportin 1, CRM-1
External IDs	OMIM: 602559 MGI: 2144013 HomoloGene: 2554 GeneCards: XPO1
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p15 Start 61,477,849 bp[1] End 61,538,626 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 A3.2 Start 23,256,041 bp[2] End 23,298,249 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein domain specific binding • transporter activity • Ran GTPase binding • GO:0001948 protein binding • RNA binding • GO:0005487 structural constituent of nuclear pore • nuclear export signal receptor activity Cellular component • cytoplasm • Cajal body • not the membrane • membrane • intracellular membrane-bounded organelle • nuclear envelope • nucleoplasm • annulate lamellae • cell nucleus • kinetochore • nucleolus • cytosol • host cell • macromolecular complex • ribonucleoprotein • intracellular Biological process • ribosomal small subunit export from nucleus • GO:0046795 intracellular transport of virus • regulation of centrosome duplication • mRNA transport • regulation of mRNA stability • negative regulation of transcription from RNA polymerase II promoter • protein export from nucleus • regulation of protein catabolic process • protein localization to nucleus • protein transport • ribosomal large subunit export from nucleus • intracellular protein transport • GO:0022415 viral process • response to drug • sister chromatid cohesion • ribosomal subunit export from nucleus • regulation of protein export from nucleus • ribosome biogenesis • transport • nucleocytoplasmic transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7514	103573
Ensembl	ENSG00000082898	ENSMUSG00000020290
UniProt	O14980	Q6P5F9
RefSeq (mRNA)	NM_003400	NM_001035226 NM_134014
RefSeq (protein)	NP_003391	NP_001030303 NP_598775
Location (UCSC)	Chr 2: 61.48 – 61.54 Mb	Chr 11: 23.26 – 23.3 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5] It was later shown to be the nuclear transport receptor for cargos with leucine-rich nuclear export signals (NES).[6][7][8][9] The structural details of the interaction of XPO1 with its cargos were revealed two decades after the gene was identified.[10][11][12][13]

Function

XPO1 mediates NES-dependent protein transport. It exports several hundreds of different proteins from the nucleus.[14][15] XPO1 is involved in the nuclear export of ribosomal subunits.[16][17][18] XPO1 plays a role in export of various RNAs including U snRNAs, rRNAs (as a part of ribosomal subunits), and some mRNAs.[19][20][21]

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.[22] XPO1 is affected in some cancer types [23] and is therefore viewed as a target for development of anti-cancer drugs.[24] Selinexor, a drug specifically targeting XPO1, was approved by the FDA for treatment of multiple myeloma.[25]

Interactions

XPO1 has been shown to interact with:

• APC,[26]
• CDKN1B,[27][28]
• CIITA,[29][30]
• NMD3,[31]
• Nucleoporin 62,[32][33]
• RANBP1,[34][35]
• RANBP3,[32][36]
• Ran,[26][34][37]
• SMARCB1,[38] and
• p53.[39][40]

See also

• Karyopherin
• Importin
• Nuclear transport
• Nuclear export signal

References

1. GRCh38: Ensembl release 89: ENSG00000082898 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020290 - 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. 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. 108 (4): 1195–1207. doi:10.1083/jcb.108.4.1195. ISSN 0021-9525.
6. 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. doi:10.1016/s0092-8674(00)80371-2. ISSN 0092-8674. PMID 9323133.
7. 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. doi:10.1038/36894. ISSN 0028-0836. PMID 9384386.
8. 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. doi:10.1016/s0092-8674(00)80370-0. ISSN 0092-8674. PMID 9323132.
9. 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. doi:10.1126/science.278.5335.141. ISSN 0036-8075. PMID 9311922.
10. 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. doi:10.1126/science.1173388. ISSN 1095-9203. PMID 19389996.
11. 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. doi:10.1038/nature07975. ISSN 1476-4687. PMC 3437623. PMID 19339969.
12. 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. doi:10.1038/nsmb.1586. ISSN 1545-9985. PMC 3437629. PMID 19339972.
13. 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. doi:10.1038/nsmb.1931. hdl:11858/00-001M-0000-0012-D4DB-B. ISSN 1545-9985. PMID 20972448.
14. 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. doi:10.1074/mcp.M112.024877. ISSN 1535-9484. PMC 3591659. PMID 23242554.
15. 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. doi:10.7554/eLife.11466. ISSN 2050-084X. PMC 4764573. PMID 26673895.
16. 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. doi:10.1101/gad.13.16.2118. ISSN 0890-9369. PMC 316945. PMID 10465789.
17. 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. doi:10.1083/jcb.151.5.1057. ISSN 0021-9525. PMC 2174350. PMID 11086007.
18. 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. doi:10.1083/jcb.200904048. ISSN 1540-8140. PMC 2712965. PMID 19564402.
19. Cullen, B. R. (June 2000). "Nuclear RNA export pathways". Molecular and Cellular Biology. 20 (12): 4181–4187. doi:10.1128/mcb.20.12.4181-4187.2000. ISSN 0270-7306. PMC 85787. PMID 10825183.
20. Köhler, Alwin; Hurt, Ed (October 2007). "Exporting RNA from the nucleus to the cytoplasm". Nature Reviews Molecular Cell Biology. 8 (10): 761–773. doi:10.1038/nrm2255. ISSN 1471-0080.
21. "Nucleocytoplasmic Transport of RNAs and RNA–Protein Complexes". Journal of Molecular Biology. 428 (10): 2040–2059. 2016-05-22. doi:10.1016/j.jmb.2015.09.023. ISSN 0022-2836.
22. Booth, David S; Cheng, Yifan; Frankel, Alan D (2014-12-08). Sundquist, Wesley I (ed.). "The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA". eLife. 3: e04121. doi:10.7554/eLife.04121. ISSN 2050-084X.
23. 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. doi:10.1158/2159-8290.CD-19-0298. ISSN 2159-8290. PMC 6774834. PMID 31285298.
24. 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. doi:10.1016/j.semcancer.2014.03.002. ISSN 1096-3650. PMC 4108548. PMID 24631835.
25. Research, Center for Drug Evaluation and (2019-12-20). "FDA grants accelerated approval to selinexor for multiple myeloma". FDA.
26. Tickenbrock L, Cramer J, Vetter IR, Muller O (August 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.
27. Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI (April 2002). "Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export". J. Biol. Chem. 277 (17): 14355–8. doi:10.1074/jbc.C100762200. PMID 11889117.
28. Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM (January 2003). "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. doi:10.1091/mbc.E02-06-0319. PMC 140238. PMID 12529437.
29. Raval A, Weissman JD, Howcroft TK, Singer DS (January 2003). "The GTP-binding domain of class II transactivator regulates its nuclear export". J. Immunol. 170 (2): 922–30. doi:10.4049/jimmunol.170.2.922. PMID 12517958.
30. Voong LN, Slater AR, Kratovac S, Cressman DE (April 2008). "Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator". J. Biol. Chem. 283 (14): 9031–9. doi:10.1074/jbc.M706487200. PMC 2431044. PMID 18245089.
31. Thomas F, Kutay U (June 2003). "Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway". J. Cell Sci. 116 (Pt 12): 2409–19. doi:10.1242/jcs.00464. PMID 12724356.
32. Lindsay ME, Holaska JM, Welch K, Paschal BM, Macara IG (June 2001). "Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export". J. Cell Biol. 153 (7): 1391–402. doi:10.1083/jcb.153.7.1391. PMC 2150735. PMID 11425870.
33. Kehlenbach RH, Dickmanns A, Kehlenbach A, Guan T, Gerace L (May 1999). "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. doi:10.1083/jcb.145.4.645. PMC 2133185. PMID 10330396.
34. Plafker K, Macara IG (May 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.
35. Singh BB, Patel HH, Roepman R, Schick D, Ferreira PA (Dec 1999). "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. doi:10.1074/jbc.274.52.37370. PMID 10601307.
36. Lindsay ME, Plafker K, Smith AE, Clurman BE, Macara IG (August 2002). "Npap60/Nup50 is a tri-stable switch that stimulates importin-alpha:beta-mediated nuclear protein import". Cell. 110 (3): 349–60. doi:10.1016/s0092-8674(02)00836-x. PMID 12176322. S2CID 15515037.
37. Fornerod M, Ohno M, Yoshida M, Mattaj IW (September 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.
38. Craig E, Zhang ZK, Davies KP, Kalpana GV (January 2002). "A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis". EMBO J. 21 (1–2): 31–42. doi:10.1093/emboj/21.1.31. PMC 125819. PMID 11782423.
39. Kanai M, Hanashiro K, Kim SH, Hanai S, Boulares AH, Miwa M, Fukasawa K (September 2007). "Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation". Nat. Cell Biol. 9 (10): 1175–83. doi:10.1038/ncb1638. PMID 17891139. S2CID 13433567.
40. Shao C, Lu C, Chen L, Koty PP, Cobos E, Gao W (August 2010). "p53-Dependent anticancer effects of leptomycin B on lung adenocarcinoma". Cancer Chemother. Pharmacol. 67 (6): 1369–80. doi:10.1007/s00280-010-1434-6. PMID 20803015. S2CID 27127578.

Further reading

• Görlich D, Kutay U (1999). "Transport between the cell nucleus and the cytoplasm". Annu. Rev. Cell Dev. Biol. 15 (1): 607–60. doi:10.1146/annurev.cellbio.15.1.607. PMID 10611974.
• Budhu AS, Wang XW (2007). "Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1". Cell Cycle. 4 (11): 1510–4. doi:10.4161/cc.4.11.2187. PMC 1402358. PMID 16294017.
• Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
• Stauber RH, Mann W, Knauer SK (2007). "Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential". Cancer Res. 67 (13): 5999–6002. doi:10.1158/0008-5472.CAN-07-0494. PMID 17616652.
• Mathew C, Ghildyal R (2017). "CRM1 inhibitors for antiviral therapy". Frontiers in Microbiology. 8: 1171. doi:10.3389/fmicb.2017.01171. PMC 5487384. PMID 28702009.

External links

• 3D electron microscopy structures of CRM1 from the EM Data Bank(EMDB)