5dis › Citations

Structural and Functional Characterization of CRM1-Nup214 Interactions Reveals Multiple FG-Binding Sites Involved in Nuclear Export.

Port SA, Monecke T, Dickmanns A, Spillner C, Hofele R, Urlaub H, Ficner R, Kehlenbach RH
Cell Rep 13 690-702 (2015)
Cited: 55 times
EuropePMC logo PMID: 26489467

Abstract

CRM1 is the major nuclear export receptor. During translocation through the nuclear pore, transport complexes transiently interact with phenylalanine-glycine (FG) repeats of multiple nucleoporins. On the cytoplasmic side of the nuclear pore, CRM1 tightly interacts with the nucleoporin Nup214. Here, we present the crystal structure of a 117-amino-acid FG-repeat-containing fragment of Nup214, in complex with CRM1, Snurportin 1, and RanGTP at 2.85 Å resolution. The structure reveals eight binding sites for Nup214 FG motifs on CRM1, with intervening stretches that are loosely attached to the transport receptor. Nup214 binds to N- and C-terminal regions of CRM1, thereby clamping CRM1 in a closed conformation and stabilizing the export complex. The role of conserved hydrophobic pockets for the recognition of FG motifs was analyzed in biochemical and cell-based assays. Comparative studies with RanBP3 and Nup62 shed light on specificities of CRM1-nucleoporin binding, which serves as a paradigm for transport receptor-nucleoporin interactions.

Reviews - 5dis mentioned but not cited (4)

  1. The Structure of the Nuclear Pore Complex (An Update). Lin DH, Hoelz A. Annu Rev Biochem 88 725-783 (2019)
  2. Floppy but not sloppy: Interaction mechanism of FG-nucleoporins and nuclear transport receptors. Aramburu IV, Lemke EA. Semin Cell Dev Biol 68 34-41 (2017)
  3. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. Camus V, Miloudi H, Taly A, Sola B, Jardin F. J Hematol Oncol 10 47 (2017)
  4. The Role of Protein Disorder in Nuclear Transport and in Its Subversion by Viruses. Wubben JM, Atkinson SC, Borg NA. Cells 9 E2654 (2020)

Articles - 5dis mentioned but not cited (3)

  1. CRM1 Promotes Capsid Disassembly and Nuclear Envelope Translocation of Adenovirus Independently of Its Export Function. Lagadec F, Carlon-Andres I, Ragues J, Port S, Wodrich H, Kehlenbach RH. J Virol 96 e0127321 (2022)
  2. Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1. Zhou J, Lei Z, Chen J, Liao S, Chen Y, Liu C, Huang S, Li L, Zhang Y, Wang P, Huang Y, Li J, Liang H. Clin Transl Med 13 e1260 (2023)
  3. A full-proteome, interaction-specific characterization of mutational hotspots across human cancers. Chen S, Liu Y, Zhang Y, Wierbowski SD, Lipkin SM, Wei X, Yu H. Genome Res 32 135-149 (2022)


Reviews citing this publication (6)

  1. The Multiple Faces of Disordered Nucleoporins. Lemke EA. J Mol Biol 428 2011-2024 (2016)
  2. NUP214 in Leukemia: It's More than Transport. Mendes A, Fahrenkrog B. Cells 8 E76 (2019)
  3. Karyopherins and condensates. Springhower CE, Rosen MK, Chook YM. Curr Opin Cell Biol 64 112-123 (2020)
  4. Synergies of Single Molecule Fluorescence and NMR for the Study of Intrinsically Disordered Proteins. Naudi-Fabra S, Blackledge M, Milles S. Biomolecules 12 27 (2021)
  5. Therapeutic Targeting of Exportin-1 in Childhood Cancer. Galinski B, Alexander TB, Mitchell DA, Chatwin HV, Awah C, Green AL, Weiser DA. Cancers (Basel) 13 6161 (2021)
  6. Nuclear transport proteins: structure, function, and disease relevance. Yang Y, Guo L, Chen L, Gong B, Jia D, Sun Q. Signal Transduct Target Ther 8 425 (2023)

Articles citing this publication (42)

  1. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Yoshizawa T, Ali R, Jiou J, Fung HYJ, Burke KA, Kim SJ, Lin Y, Peeples WB, Saltzberg D, Soniat M, Baumhardt JM, Oldenbourg R, Sali A, Fawzi NL, Rosen MK, Chook YM. Cell 173 693-705.e22 (2018)
  2. Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE. J Clin Oncol 34 4094-4101 (2016)
  3. Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex. Raveh B, Karp JM, Sparks S, Dutta K, Rout MP, Sali A, Cowburn D. Proc Natl Acad Sci U S A 113 E2489-97 (2016)
  4. On the role of phase separation in the biogenesis of membraneless compartments. Musacchio A. EMBO J 41 e109952 (2022)
  5. The RanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 ligase is a disassembly machine for Crm1-dependent nuclear export complexes. Ritterhoff T, Das H, Hofhaus G, Schröder RR, Flotho A, Melchior F. Nat Commun 7 11482 (2016)
  6. A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies. Zahn R, Osmanović D, Ehret S, Araya Callis C, Frey S, Stewart M, You C, Görlich D, Hoogenboom BW, Richter RP. Elife 5 e14119 (2016)
  7. Multiple components of the nuclear pore complex interact with the amino-terminus of MX2 to facilitate HIV-1 restriction. Dicks MDJ, Betancor G, Jimenez-Guardeño JM, Pessel-Vivares L, Apolonia L, Goujon C, Malim MH. PLoS Pathog 14 e1007408 (2018)
  8. Two Differential Binding Mechanisms of FG-Nucleoporins and Nuclear Transport Receptors. Tan PS, Aramburu IV, Mercadante D, Tyagi S, Chowdhury A, Spitz D, Shammas SL, Gräter F, Lemke EA. Cell Rep 22 3660-3671 (2018)
  9. Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. Oka M, Mura S, Otani M, Miyamoto Y, Nogami J, Maehara K, Harada A, Tachibana T, Yoneda Y, Ohkawa Y. Elife 8 e46667 (2019)
  10. Spatial structure of disordered proteins dictates conductance and selectivity in nuclear pore complex mimics. Ananth AN, Mishra A, Frey S, Dwarkasing A, Versloot R, van der Giessen E, Görlich D, Onck P, Dekker C. Elife 7 (2018)
  11. Molecular determinants of large cargo transport into the nucleus. Paci G, Zheng T, Caria J, Zilman A, Lemke EA. Elife 9 e55963 (2020)
  12. The RNA-binding protein FUS is chaperoned and imported into the nucleus by a network of import receptors. Baade I, Hutten S, Sternburg EL, Pörschke M, Hofweber M, Dormann D, Kehlenbach RH. J Biol Chem 296 100659 (2021)
  13. Extensive Identification and In-depth Validation of Importin 13 Cargoes. Baade I, Spillner C, Schmitt K, Valerius O, Kehlenbach RH. Mol Cell Proteomics 17 1337-1353 (2018)
  14. 8 Å structure of the outer rings of the Xenopus laevis nuclear pore complex obtained by cryo-EM and AI. Tai L, Zhu Y, Ren H, Huang X, Zhang C, Sun F. Protein Cell 13 760-777 (2022)
  15. Human PDCD2L Is an Export Substrate of CRM1 That Associates with 40S Ribosomal Subunit Precursors. Landry-Voyer AM, Bilodeau S, Bergeron D, Dionne KL, Port SA, Rouleau C, Boisvert FM, Kehlenbach RH, Bachand F. Mol Cell Biol 36 3019-3032 (2016)
  16. Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation. Baumhardt JM, Walker JS, Lee Y, Shakya B, Brautigam CA, Lapalombella R, Grishin N, Chook YM. Mol Biol Cell 31 1879-1891 (2020)
  17. Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore. Bao XX, Spanos C, Kojidani T, Lynch EM, Rappsilber J, Hiraoka Y, Haraguchi T, Sawin KE. Elife 7 e33465 (2018)
  18. Karyopherin enrichment and compensation fortifies the nuclear pore complex against nucleocytoplasmic leakage. Kalita J, Kapinos LE, Zheng T, Rencurel C, Zilman A, Lim RYH. J Cell Biol 221 e202108107 (2022)
  19. The Oncogenic Fusion Proteins SET-Nup214 and Sequestosome-1 (SQSTM1)-Nup214 Form Dynamic Nuclear Bodies and Differentially Affect Nuclear Protein and Poly(A)+ RNA Export. Port SA, Mendes A, Valkova C, Spillner C, Fahrenkrog B, Kaether C, Kehlenbach RH. J Biol Chem 291 23068-23083 (2016)
  20. Deciphering the "Fuzzy" Interaction of FG Nucleoporins and Transport Factors Using Small-Angle Neutron Scattering. Sparks S, Temel DB, Rout MP, Cowburn D. Structure 26 477-484.e4 (2018)
  21. The path of pre-ribosomes through the nuclear pore complex revealed by electron tomography. Delavoie F, Soldan V, Rinaldi D, Dauxois JY, Gleizes PE. Nat Commun 10 497 (2019)
  22. A simple thermodynamic description of phase separation of Nup98 FG domains. Ng SC, Görlich D. Nat Commun 13 6172 (2022)
  23. Nup358 and Transportin 1 Cooperate in Adenoviral Genome Import. Carlon-Andres I, Lagadec F, Pied N, Rayne F, Lafon ME, Kehlenbach RH, Wodrich H. J Virol 94 e00164-20 (2020)
  24. XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-cell Lymphoma. Miloudi H, Bohers É, Guillonneau F, Taly A, Gibouin VC, Viailly PJ, Jego G, Grumolato L, Jardin F, Sola B. Cancers (Basel) 12 E2829 (2020)
  25. Titanium Dioxide Nanoparticles Alter the Cellular Phosphoproteome in A549 Cells. Biola-Clier M, Gaillard JC, Rabilloud T, Armengaud J, Carriere M. Nanomaterials (Basel) 10 E185 (2020)
  26. Host Factor Nucleoporin 93 Is Involved in the Nuclear Export of Influenza Virus RNA. Furusawa Y, Yamada S, Kawaoka Y. Front Microbiol 9 1675 (2018)
  27. Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1). Rahmani K, Dean DA. Biochem Biophys Res Commun 488 253-258 (2017)
  28. Interactions of nuclear transport factors and surface-conjugated FG nucleoporins: Insights and limitations. Hayama R, Sorci M, Keating Iv JJ, Hecht LM, Plawsky JL, Belfort G, Chait BT, Rout MP. PLoS One 14 e0217897 (2019)
  29. Crystal structure of the Xpo1p nuclear export complex bound to the SxFG/PxFG repeats of the nucleoporin Nup42p. Koyama M, Hirano H, Shirai N, Matsuura Y. Genes Cells 22 861-875 (2017)
  30. Nucleoporin foci are stress-sensitive condensates dispensable for C. elegans nuclear pore assembly. Thomas L, Taleb Ismail B, Askjaer P, Seydoux G. EMBO J 42 e112987 (2023)
  31. Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length. Ng SC, Biswas A, Huyton T, Schünemann J, Reber S, Görlich D. Nat Commun 14 747 (2023)
  32. Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors. Jafarinia H, Van der Giessen E, Onck PR. Sci Rep 12 21324 (2022)
  33. Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements. Mendes A, Jühlen R, Martinelli V, Fahrenkrog B. Oncotarget 11 3371-3386 (2020)
  34. The SQSTM1-NUP214 fusion protein interacts with Crm1, activates Hoxa and Meis1 genes, and drives leukemogenesis in mice. Lavau CP, Aumann WK, Sze SK, Gupta V, Ripple K, Port SA, Kehlenbach RH, Wechsler DS. PLoS One 15 e0232036 (2020)
  35. The nuclear lamina is a hub for the nuclear function of Jacob. Samer S, Raman R, Laube G, Kreutz MR, Karpova A. Mol Brain 14 9 (2021)
  36. Crystal structure of human CRM1, covalently modified by 2-mercaptoethanol on Cys528, in complex with RanGTP. Shaikhqasem A, Schmitt K, Valerius O, Ficner R. Acta Crystallogr F Struct Biol Commun 77 70-78 (2021)
  37. Letter Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes. Aumann WK, Heath JL, Conway AE, Sze SK, Gupta VK, Kazi RR, Tope DR, Wechsler DS, Lavau CP. Leukemia 35 876-880 (2021)
  38. Probing Differential Binding Mechanisms of Phenylalanine-Glycine-Rich Nucleoporins by Single-Molecule FRET. Tan PS, Lemke EA. Methods Enzymol 611 327-346 (2018)
  39. Combining dehydration, construct optimization and improved data collection to solve the crystal structure of a CRM1-RanGTP-SPN1-Nup214 quaternary nuclear export complex. Monecke T, Dickmanns A, Weiss MS, Port SA, Kehlenbach RH, Ficner R. Acta Crystallogr F Struct Biol Commun 71 1481-1487 (2015)
  40. Karyopherins in the Remodeling of Extracellular Matrix: Implications in Tendon Injury. Diaz C, Thankam FG, Agrawal DK. J Orthop Sports Med 5 357-374 (2023)
  41. Transportin 1 is a major nuclear import receptor of the nitric oxide synthase interacting protein. Pörschke M, Rodríguez-González I, Parfentev I, Urlaub H, Kehlenbach RH. J Biol Chem 299 102932 (2023)
  42. Unusual Presentation of SET::NUP214-Associated Concomitant Hematological Neoplasm in a Child-Diagnostic and Treatment Struggle. Menchits Y, Salimova T, Komkov A, Abramov D, Konyukhova T, Abasov R, Raykina E, Itov A, Gaskova M, Borkovskaia A, Kazakova A, Soldatkina O, Kashpor S, Semchenkova A, Popov A, Novichkova G, Olshanskaya Y, Maschan A, Zerkalenkova E. Int J Mol Sci 24 14451 (2023)


Related citations provided by authors (1)

  1. Combining dehydration, construct optimization and improved data collection to solve the crystal structure of a CRM1-RanGTP-SPN1-Nup214 quaternary export complex. Monecke T, Dickmanns A, Weiss MS, Port SA, Kehlenbach RH, Ficner R To be published -

Quick links