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The Quest for the Blueprint of the Nuclear Pore Complex

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Abstract

During my postdoc interview in June of 1998, I asked Günter why he was moving more towards the nucleus in his latest studies. He said, “Well Joe, that’s where everything starts.” By the end of the interview, I accepted the postdoc. He had a way of making everything sound so cool. Günter’s progression was natural, since the endoplasmic reticulum and the nucleus are the only organelles that share the same membrane. The nuclear envelope extends into a double membrane system with nuclear pore complexes embedded in the pore membrane openings. Even while writing this review, I remember Günter stressing; it is the nuclear pore complex. Just saying nuclear pore doesn’t encompass the full magnitude of its significance. The nuclear pore complex is one of the largest collection of proteins that fit together for an overall function: transport. This review will cover the Blobel lab contributions in the quest for the blueprint of the nuclear pore complex from isolation of the nuclear envelope and nuclear lamin to the ring structures.

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(Adapted from Monneron et al. [26])

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References

  1. Hoelz A, Glavy JS, Beck M (2016) Toward the atomic structure of the nuclear pore complex: when top down meets bottom up. Nat Struct Mol Biol 23(7):624–630. https://doi.org/10.1038/nsmb.3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lusk CP, Blobel G, King MC (2007) Highway to the inner nuclear membrane: rules for the road. Nat Rev Mol Cell Biol 8(5):414–420. https://doi.org/10.1038/nrm2165

    Article  CAS  PubMed  Google Scholar 

  3. Lin DH, Hoelz A (2019) The Structure of the nuclear pore complex (an update). Annu Rev Biochem 88:725–783. https://doi.org/10.1146/annurev-biochem-062917-011901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tran EJ, Wente SR (2006) Dynamic nuclear pore complexes: life on the edge. Cell 125(6):1041–1053

    Article  CAS  PubMed  Google Scholar 

  5. Hoelz A, Debler EW, Blobel G (2011) The structure of the nuclear pore complex. Annu Rev Biochem 80:613–643. https://doi.org/10.1146/annurev-biochem-060109-151030

    Article  CAS  PubMed  Google Scholar 

  6. Gall JG (1954) Observations on the nuclear membrane with the electron microscope. Exp Cell Res 7(1):197–200

    Article  CAS  PubMed  Google Scholar 

  7. Weis K (2003) Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell 112(4):441–451

    Article  CAS  PubMed  Google Scholar 

  8. Moore MS, Blobel G (1993) The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature 365(6447):661–663. https://doi.org/10.1038/365661a0

    Article  CAS  PubMed  Google Scholar 

  9. Hoelz A, Blobel G (2004) Cell biology: popping out of the nucleus. Nature 432(7019):815–816. https://doi.org/10.1038/432815a

    Article  CAS  PubMed  Google Scholar 

  10. Hatch E, Hetzer M (2014) Breaching the nuclear envelope in development and disease. J Cell Biol 205(2):133–141. https://doi.org/10.1083/jcb.201402003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yamauchi Y, Helenius A (2013) Virus entry at a glance. J Cell Sci 126(Pt 6):1289–1295. https://doi.org/10.1242/jcs.119685

    Article  CAS  PubMed  Google Scholar 

  12. Strunze S, Engelke MF, Wang IH, Puntener D, Boucke K, Schleich S, Way M, Schoenenberger P, Burckhardt CJ, Greber UF (2011) Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 10(3):210–223. https://doi.org/10.1016/j.chom.2011.08.010

    Article  CAS  PubMed  Google Scholar 

  13. Campbell EM, Hope TJ (2015) HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13(8):471–483. https://doi.org/10.1038/nrmicro3503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blobel G, Potter VR (1966) Nuclei from rat liver: isolation method that combines purity with high yield. Science 154(3757):1662–1665

    Article  CAS  Google Scholar 

  15. Maggio R, Siekevitz P, Palade GE (1963) Studies on isolated nuclei. Ii. Isolation and chemical characterization of nucleolar and nucleoplasmic subfractions. J Cell Biol 18:293–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maggio R, Siekevitz P, Palade GE (1963) Studies on isolated nuclei. I. Isolation and chemical characterization of a nuclear fraction from guinea pig liver. J Cell Biol 18:267–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chauveau J, Moule Y, Rouiller C (1956) Isolation of pure and unaltered liver nuclei morphology and biochemical composition. Exp Cell Res 11(2):317–321

    Article  CAS  PubMed  Google Scholar 

  18. Kashnig DM, Kasper CB (1969) Isolation, morphology, and composition of the nuclear membrane from rat liver. J Biol Chem 244(14):3786–3792

    CAS  PubMed  Google Scholar 

  19. Franke WW, Deumling B, Baerbelermen Jarasch ED, Kleinig H (1970) Nuclear membranes from mammalian liver. I. Isolation procedure and general characterization. J Cell Biol 46(2):379–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Berezney R, Funk LK, Crane FL (1970) Electron transport in mammalian nuclei. II. Oxidative enzmes in a large-scale preparation of bovine liver nuclei. Biochim Biophys Acta 223(1):61–70

    Article  CAS  PubMed  Google Scholar 

  21. Berezney R, Funk LK, Crane FL (1970) The isolation of nuclear membrane from a large-scale preparation of bovine liver nuclei. Biochim Biophys Acta 203(3):531–546

    Article  CAS  PubMed  Google Scholar 

  22. Berezney R, Funk LK, Crane FL (1970) Nuclear electron transport. I. Electron transport enzymes in bovine liver nuclei and nuclear membrane. Biochem Biophys Res Commun 38(1):93–98

    Article  CAS  PubMed  Google Scholar 

  23. Keenan TW, Berezney R, Funk LK, Crane FL (1970) Lipid composition of nuclear membranes isolated from bovine liver. Biochim Biophys Acta 203(3):547–554

    Article  CAS  PubMed  Google Scholar 

  24. Ueda K, Matsuura T, Date N, Kawai K (1969) The occurrence of cytochromes in the membranous structures of calf thymus nuclei. Biochem Biophys Res Commun 34(3):322–327

    Article  CAS  PubMed  Google Scholar 

  25. Zbarsky IB, Perevoshchikova KA, Delektorskaya LN, Delektorsky VV (1969) Isolation and biochemical characteristics of the nuclear envelope. Nature 221(5177):257–259

    Article  CAS  PubMed  Google Scholar 

  26. Monneron A, Blobel G, Palade GE (1972) Fractionation of the nucleus by divalent cations. Isolation of nuclear membranes. J Cell Biol 55(1):104–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Scheer U, Kartenbeck J, Trendelenburg MF, Stadler J, Franke WW (1976) Experimental disintegration of the nuclear envelope. Evidence for pore-connecting fibrils. J Cell Biol 69(1):1–18

    Article  CAS  PubMed  Google Scholar 

  28. Aaronson RP, Blobel G (1974) On the attachment of the nuclear pore complex. J Cell Biol 62(3):746–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Aaronson RP, Blobel G (1975) Isolation of nuclear pore complexes in association with a lamina. Proc Natl Acad Sci USA 72(3):1007–1011

    Article  CAS  PubMed  Google Scholar 

  30. Berezney R (1974) Large-scale isolation of nuclear membranes from bovine liver. Methods Cell Biol 8:205–228

    Article  CAS  PubMed  Google Scholar 

  31. Berezney R, Coffey DS (1974) Identification of a nuclear protein matrix. Biochem Biophys Res Commun 60(4):1410–1417

    Article  CAS  PubMed  Google Scholar 

  32. Watson ML (1954) Pores in the mammalian nuclear membrane. Biochim Biophys Acta 15(4):475–479

    Article  CAS  PubMed  Google Scholar 

  33. Watson ML (1955) The nuclear envelope; its structure and relation to cytoplasmic membranes. J Biophys Biochem Cytol 1(3):257–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Patrizi G, Poger M (1967) The ultrastructure of the nuclear periphery. The zonula nucleum limitans. J Ultrastruct Res 17(1):127–136

    Article  CAS  PubMed  Google Scholar 

  35. Diguilio AL, Glavy JS (2013) Depletion of nucleoporins from HeLa nuclear pore complexes to facilitate the production of ghost pores for in vitro reconstitution. Cytotechnology 65(4):469–479. https://doi.org/10.1007/s10616-012-9501-y

    Article  CAS  PubMed  Google Scholar 

  36. Dwyer N, Blobel G (1976) A modified procedure for the isolation of a pore complex-lamina fraction from rat liver nuclei. J Cell Biol 70(3):581–591

    Article  CAS  PubMed  Google Scholar 

  37. Gall JG (1967) Octagonal nuclear pores. J Cell Biol 32(2):391–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beck M, Forster F, Ecke M, Plitzko JM, Melchior F, Gerisch G, Baumeister W, Medalia O (2004) Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 306(5700):1387–1390. https://doi.org/10.1126/science.1104808

    Article  CAS  PubMed  Google Scholar 

  39. Beck M, Lucic V, Forster F, Baumeister W, Medalia O (2007) Snapshots of nuclear pore complexes in action captured by cryo-electron tomography. Nature 449(7162):611–615. https://doi.org/10.1038/nature06170

    Article  CAS  PubMed  Google Scholar 

  40. Bui KH, von Appen A, Diguilio AL, Ori A, Sparks L, Mackmull MT, Bock T, Hagen W, Andres-Pons A, Glavy JS, Beck M (2013) Integrated structural analysis of the human nuclear pore complex scaffold. Cell 155(6):1233–1243. https://doi.org/10.1016/j.cell.2013.10.055

    Article  CAS  PubMed  Google Scholar 

  41. Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M (2016) Molecular architecture of the inner ring scaffold of the human nuclear pore complex. Science 352(6283):363–365. https://doi.org/10.1126/science.aaf0643

    Article  CAS  PubMed  Google Scholar 

  42. Beck M, Glavy JS (2014) Toward understanding the structure of the vertebrate nuclear pore complex. Nucleus 5(2):119–123

    Article  PubMed  PubMed Central  Google Scholar 

  43. von Appen A, Kosinski J, Sparks L, Ori A, DiGuilio AL, Vollmer B, Mackmull MT, Banterle N, Parca L, Kastritis P, Buczak K, Mosalaganti S, Hagen W, Andres-Pons A, Lemke EA, Bork P, Antonin W, Glavy JS, Bui KH, Beck M (2015) In situ structural analysis of the human nuclear pore complex. Nature 526(7571):140–143. https://doi.org/10.1038/nature15381

    Article  CAS  Google Scholar 

  44. Kay RR, Fraser D, Johnston IR (1972) A method for the rapid isolation of nuclear membranes from rat liver. Characterisation of the membrane preparation and its associated DNA polymerase. Eur J Biochem 30(1):145–154

    Article  CAS  PubMed  Google Scholar 

  45. Gerace L, Blum A, Blobel G (1978) Immunocytochemical localization of the major polypeptides of the nuclear pore complex-lamina fraction Interphase and mitotic distribution. J Cell Biol 79(2 Pt 1):546–566

    Article  CAS  PubMed  Google Scholar 

  46. Gerace L, Blobel G (1980) The nuclear envelope lamina is reversibly depolymerized during mitosis. Cell 19(1):277–287

    Article  CAS  PubMed  Google Scholar 

  47. Fisher DZ, Chaudhary N, Blobel G (1986) cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc Natl Acad Sci USA 83(17):6450–6454

    Article  CAS  PubMed  Google Scholar 

  48. Worman HJ, Lazaridis I, Georgatos SD (1988) Nuclear lamina heterogeneity in mammalian cells. Differential expression of the major lamins and variations in lamin B phosphorylation. J Biol Chem 263(24):12135–12141

    CAS  PubMed  Google Scholar 

  49. Worman HJ, Yuan J, Blobel G, Georgatos SD (1988) A lamin B receptor in the nuclear envelope. Proc Natl Acad Sci USA 85(22):8531–8534

    Article  CAS  PubMed  Google Scholar 

  50. Georgatos SD, Blobel G (1987) Lamin B constitutes an intermediate filament attachment site at the nuclear envelope. J Cell Biol 105(1):117–125

    Article  CAS  PubMed  Google Scholar 

  51. Georgatos SD, Weber K, Geisler N, Blobel G (1987) Binding of two desmin derivatives to the plasma membrane and the nuclear envelope of avian erythrocytes: evidence for a conserved site-specificity in intermediate filament-membrane interactions. Proc Natl Acad Sci USA 84(19):6780–6784

    Article  CAS  PubMed  Google Scholar 

  52. Djabali K, Portier MM, Gros F, Blobel G, Georgatos SD (1991) Network antibodies identify nuclear lamin B as a physiological attachment site for peripherin intermediate filaments. Cell 64(1):109–121

    Article  CAS  PubMed  Google Scholar 

  53. Appelbaum J, Blobel G, Georgatos SD (1990) In vivo phosphorylation of the lamin B receptor. Binding of lamin B to its nuclear membrane receptor is affected by phosphorylation. J Biol Chem 265(8):4181–4184

    CAS  PubMed  Google Scholar 

  54. Blobel G (1985) Gene gating: a hypothesis. Proc Natl Acad Sci USA 82(24):8527–8529

    Article  CAS  PubMed  Google Scholar 

  55. Davis LI, Blobel G (1986) Identification and characterization of a nuclear pore complex protein. Cell 45(5):699–709

    Article  CAS  PubMed  Google Scholar 

  56. Davis LI, Blobel G (1987) Nuclear pore complex contains a family of glycoproteins that includes p62: glycosylation through a previously unidentified cellular pathway. Proc Natl Acad Sci USA 84(21):7552–7556

    Article  CAS  PubMed  Google Scholar 

  57. Wente SR, Rout MP, Blobel G (1992) A new family of yeast nuclear pore complex proteins. J Cell Biol 119(4):705–723

    Article  CAS  PubMed  Google Scholar 

  58. Wente SR, Blobel G (1993) A temperature-sensitive NUP116 null mutant forms a nuclear envelope seal over the yeast nuclear pore complex thereby blocking nucleocytoplasmic traffic. J Cell Biol 123(2):275–284

    Article  CAS  PubMed  Google Scholar 

  59. Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW (1990) The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest 86(1):279–285. https://doi.org/10.1172/JCI114696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wozniak RW, Blobel G (1992) The single transmembrane segment of gp210 is sufficient for sorting to the pore membrane domain of the nuclear envelope. J Cell Biol 119(6):1441–1449

    Article  CAS  PubMed  Google Scholar 

  61. Hallberg E, Wozniak RW, Blobel G (1993) An integral membrane protein of the pore membrane domain of the nuclear envelope contains a nucleoporin-like region. J Cell Biol 122(3):513–521

    Article  CAS  PubMed  Google Scholar 

  62. Radu A, Blobel G, Wozniak RW (1993) Nup155 is a novel nuclear pore complex protein that contains neither repetitive sequence motifs nor reacts with WGA. J Cell Biol 121(1):1–9

    Article  CAS  PubMed  Google Scholar 

  63. Kraemer D, Wozniak RW, Blobel G, Radu A (1994) The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proc Natl Acad Sci USA 91(4):1519–1523

    Article  CAS  PubMed  Google Scholar 

  64. Radu A, Blobel G, Wozniak RW (1994) Nup107 is a novel nuclear pore complex protein that contains a leucine zipper. J Biol Chem 269(26):17600–17605

    CAS  PubMed  Google Scholar 

  65. Glavy JS, Krutchinsky AN, Cristea IM, Berke IC, Boehmer T, Blobel G, Chait BT (2007) Cell-cycle-dependent phosphorylation of the nuclear pore Nup107-160 subcomplex. Proc Natl Acad Sci USA 104(10):3811–3816. https://doi.org/10.1073/pnas.0700058104

    Article  CAS  PubMed  Google Scholar 

  66. Rout MP, Aitchison JD, Suprapto A, Hjertaas K, Zhao Y, Chait BT (2000) The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol 148(4):635–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ (2002) Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol 158(5):915–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rout MP, Blobel G (1993) Isolation of the yeast nuclear pore complex. J Cell Biol 123(4):771–783

    Article  CAS  PubMed  Google Scholar 

  69. Matunis MJ (2006) Isolation and fractionation of rat liver nuclear envelopes and nuclear pore complexes. Methods 39(4):277–283. https://doi.org/10.1016/j.ymeth.2006.06.003

    Article  CAS  PubMed  Google Scholar 

  70. von Appen A, Beck M (2016) Structure Determination of the nuclear pore complex with three-dimensional cryo electron microscopy. J Mol Biol 428(10 Pt A):2001–2010. https://doi.org/10.1016/j.jmb.2016.01.004

    Article  CAS  Google Scholar 

  71. Ori A, Banterle N, Iskar M, Andres-Pons A, Escher C, Khanh Bui H, Sparks L, Solis-Mezarino V, Rinner O, Bork P, Lemke EA, Beck M (2013) Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines. Mol Syst Biol 9:648. https://doi.org/10.1038/msb.2013.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rasala BA, Orjalo AV, Shen Z, Briggs S, Forbes DJ (2006) ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division. Proc Natl Acad Sci USA 103(47):17801–17806. https://doi.org/10.1073/pnas.0608484103

    Article  CAS  PubMed  Google Scholar 

  73. Franz C, Walczak R, Yavuz S, Santarella R, Gentzel M, Askjaer P, Galy V, Hetzer M, Mattaj IW, Antonin W (2007) MEL-28/ELYS is required for the recruitment of nucleoporins to chromatin and postmitotic nuclear pore complex assembly. EMBO Rep 8(2):165–172. https://doi.org/10.1038/sj.embor.7400889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cristea IM, Williams R, Chait BT, Rout MP (2005) Fluorescent proteins as proteomic probes. Mol Cell Proteomics 4(12):1933–1941

    Article  CAS  PubMed  Google Scholar 

  75. Kampmann M, Blobel G (2009) Three-dimensional structure and flexibility of a membrane-coating module of the nuclear pore complex. Nat Struct Mol Biol 16(7):782–788. https://doi.org/10.1038/nsmb.1618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lin DH, Stuwe T, Schilbach S, Rundlet EJ, Perriches T, Mobbs G, Fan Y, Thierbach K, Huber FM, Collins LN, Davenport AM, Jeon YE, Hoelz A (2016) Architecture of the symmetric core of the nuclear pore. Science 352(6283):aaf1015. https://doi.org/10.1126/science.aaf1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Stuwe T, Correia AR, Lin DH, Paduch M, Lu VT, Kossiakoff AA, Hoelz A (2015) Nuclear pores. Architecture of the nuclear pore complex coat. Science 347(6226):1148–1152. https://doi.org/10.1126/science.aaa4136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lutzmann M, Kunze R, Buerer A, Aebi U, Hurt E (2002) Modular self-assembly of a Y-shaped multiprotein complex from seven nucleoporins. EMBO J 21(3):387–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Siniossoglou S, Lutzmann M, Santos-Rosa H, Leonard K, Mueller S, Aebi U, Hurt E (2000) Structure and assembly of the Nup84p complex. J Cell Biol 149(1):41–54. https://doi.org/10.1083/jcb.149.1.41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos DP, Cristea IM, Williams R, Salamero J, Chait BT, Sali A, Field MC, Rout MP, Dargemont C (2011) A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol Cell Proteomics 10(6):478. https://doi.org/10.1074/mcp.m110.006478

    Article  Google Scholar 

  81. Dokudovskaya S, Rout MP (2011) A novel coatomer-related SEA complex dynamically associates with the vacuole in yeast and is implicated in the response to nitrogen starvation. Autophagy 7(11):1392–1393. https://doi.org/10.4161/auto.7.11.17347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Berke IC, Boehmer T, Blobel G, Schwartz TU (2004) Structural and functional analysis of Nup133 domains reveals modular building blocks of the nuclear pore complex. J Cell Biol 167(4):591–597. https://doi.org/10.1083/jcb.200408109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Boehmer T, Jeudy S, Berke IC, Schwartz TU (2008) Structural and functional studies of Nup107/Nup133 interaction and its implications for the architecture of the nuclear pore complex. Mol Cell 30(6):721–731. https://doi.org/10.1016/j.molcel.2008.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nagy V, Hsia KC, Debler EW, Kampmann M, Davenport AM, Blobel G, Hoelz A (2009) Structure of a trimeric nucleoporin complex reveals alternate oligomerization states. Proc Natl Acad Sci USA 106(42):17693–17698. https://doi.org/10.1073/pnas.0909373106

    Article  PubMed  Google Scholar 

  85. Debler EW, Ma Y, Seo HS, Hsia KC, Noriega TR, Blobel G, Hoelz A (2008) A fence-like coat for the nuclear pore membrane. Mol Cell 32(6):815–826. https://doi.org/10.1016/j.molcel.2008.12.001

    Article  CAS  PubMed  Google Scholar 

  86. Hsia KC, Stavropoulos P, Blobel G, Hoelz A (2007) Architecture of a coat for the nuclear pore membrane. Cell 131(7):1313–1326. https://doi.org/10.1016/j.cell.2007.11.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hawryluk-Gara LA, Shibuya EK, Wozniak RW (2005) Vertebrate Nup53 interacts with the nuclear lamina and is required for the assembly of a Nup93-containing complex. Mol Biol Cell 16(5):2382–2394. https://doi.org/10.1091/mbc.E04-10-0857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jeudy S, Schwartz TU (2007) Crystal structure of nucleoporin Nic96 reveals a novel, intricate helical domain architecture. J Biol Chem 282(48):34904–34912. https://doi.org/10.1074/jbc.M705479200

    Article  CAS  PubMed  Google Scholar 

  89. Stuwe T, Lin DH, Collins LN, Hurt E, Hoelz A (2014) Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins. Proc Natl Acad Sci USA 111(7):2530–2535. https://doi.org/10.1073/pnas.1311081111

    Article  CAS  PubMed  Google Scholar 

  90. Antonin W, Ellenberg J, Dultz E (2008) Nuclear pore complex assembly through the cell cycle: regulation and membrane organization. FEBS Lett 582(14):2004–2016. https://doi.org/10.1016/j.febslet.2008.02.067

    Article  CAS  PubMed  Google Scholar 

  91. Lim RY, Aebi U, Fahrenkrog B (2008) Towards reconciling structure and function in the nuclear pore complex. Histochem Cell Biol 129(2):105–116. https://doi.org/10.1007/s00418-007-0371-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kita K, Omata S, Horigome T (1993) Purification and characterization of a nuclear pore glycoprotein complex containing p62. J Biochem 113(3):377–382. https://doi.org/10.1093/oxfordjournals.jbchem.a124054

    Article  CAS  PubMed  Google Scholar 

  93. Strawn LA, Shen T, Shulga N, Goldfarb DS, Wente SR (2004) Minimal nuclear pore complexes define FG repeat domains essential for transport. Nat Cell Biol 6(3):197–206. https://doi.org/10.1038/ncb1097

    Article  CAS  PubMed  Google Scholar 

  94. Schwartz TU (2005) Modularity within the architecture of the nuclear pore complex. Curr Opin Struct Biol 15(2):221–226

    Article  CAS  PubMed  Google Scholar 

  95. Melcak I, Hoelz A, Blobel G (2007) Structure of Nup58/45 suggests flexible nuclear pore diameter by intermolecular sliding. Science 315(5819):1729–1732. https://doi.org/10.1126/science.1135730

    Article  CAS  PubMed  Google Scholar 

  96. Chug H, Trakhanov S, Hulsmann BB, Pleiner T, Gorlich D (2015) Crystal structure of the metazoan Nup62*Nup58*Nup54 nucleoporin complex. Science 350(6256):106–110. https://doi.org/10.1126/science.aac7420

    Article  CAS  PubMed  Google Scholar 

  97. Denning DP, Patel SS, Uversky V, Fink AL, Rexach M (2003) Disorder in the nuclear pore complex: the FG repeat regions of nucleoporins are natively unfolded. Proc Natl Acad Sci USA 100(5):2450–2455. https://doi.org/10.1073/pnas.0437902100

    Article  CAS  PubMed  Google Scholar 

  98. Timney BL, Raveh B, Mironska R, Trivedi JM, Kim SJ, Russel D, Wente SR, Sali A, Rout MP (2016) Simple rules for passive diffusion through the nuclear pore complex. J Cell Biol 215(1):57–76. https://doi.org/10.1083/jcb.201601004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Krull S, Thyberg J, Bjorkroth B, Rackwitz HR, Cordes VC (2004) Nucleoporins as components of the nuclear pore complex core structure and Tpr as the architectural element of the nuclear basket. Mol Biol Cell 15(9):4261–4277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. McCloskey A, Ibarra A, Hetzer MW (2018) Tpr regulates the total number of nuclear pore complexes per cell nucleus. Genes Dev 32(19–20):1321–1331. https://doi.org/10.1101/gad.315523.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hase ME, Cordes VC (2003) Direct interaction with nup153 mediates binding of Tpr to the periphery of the nuclear pore complex. Mol Biol Cell 14(5):1923–1940. https://doi.org/10.1091/mbc.E02-09-0620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rajanala K, Nandicoori VK (2012) Localization of nucleoporin Tpr to the nuclear pore complex is essential for Tpr mediated regulation of the export of unspliced RNA. PLoS ONE 7(1):e29921. https://doi.org/10.1371/journal.pone.0029921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rajanala K, Sarkar A, Jhingan GD, Priyadarshini R, Jalan M, Sengupta S, Nandicoori VK (2014) Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function. J Cell Sci 127(Pt 16):3505–3520. https://doi.org/10.1242/jcs.149112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Coyle JH, Bor YC, Rekosh D, Hammarskjold ML (2011) The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway. RNA 17(7):1344–1356. https://doi.org/10.1261/rna.2616111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Makise M, Mackay DR, Elgort S, Shankaran SS, Adam SA, Ullman KS (2012) The Nup153-Nup50 protein interface and its role in nuclear import. J Biol Chem 287(46):38515–38522. https://doi.org/10.1074/jbc.M112.378893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Napetschnig J, Blobel G, Hoelz A (2007) Crystal structure of the N-terminal domain of the human protooncogene Nup214/CAN. Proc Natl Acad Sci USA 104(6):1783–1788. https://doi.org/10.1073/pnas.0610828104

    Article  CAS  PubMed  Google Scholar 

  107. Fontoura BM, Blobel G, Matunis MJ (1999) A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin, Nup96. J Cell Biol 144(6):1097–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Fontoura BM, Blobel G, Yaseen NR (2000) The nucleoporin Nup98 is a site for GDP/GTP exchange on ran and termination of karyopherin beta 2-mediated nuclear import. J Biol Chem 275(40):31289–31296. https://doi.org/10.1074/jbc.M004651200

    Article  CAS  PubMed  Google Scholar 

  109. Fontoura BM, Dales S, Blobel G, Zhong H (2001) The nucleoporin Nup98 associates with the intranuclear filamentous protein network of TPR. Proc Natl Acad Sci USA 98(6):3208–3213. https://doi.org/10.1073/pnas.061014698

    Article  CAS  PubMed  Google Scholar 

  110. Tamura K, Fukao Y, Iwamoto M, Haraguchi T, Hara-Nishimura I (2010) Identification and characterization of nuclear pore complex components in Arabidopsis thaliana. Plant Cell 22(12):4084–4097. https://doi.org/10.1105/tpc.110.079947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chakraborty P, Wang Y, Wei JH, van Deursen J, Yu H, Malureanu L, Dasso M, Forbes DJ, Levy DE, Seemann J, Fontoura BM (2008) Nucleoporin levels regulate cell cycle progression and phase-specific gene expression. Dev Cell 15(5):657–667. https://doi.org/10.1016/j.devcel.2008.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chakraborty P, Seemann J, Mishra RK, Wei JH, Weil L, Nussenzveig DR, Heiber J, Barber GN, Dasso M, Fontoura BM (2009) Vesicular stomatitis virus inhibits mitotic progression and triggers cell death. EMBO Rep 10(10):1154–1160. https://doi.org/10.1038/embor.2009.179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liang Y, Franks TM, Marchetto MC, Gage FH, Hetzer MW (2013) Dynamic association of NUP98 with the human genome. PLoS Genet 9(2):e1003308. https://doi.org/10.1371/journal.pgen.1003308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mor A, White MA, Fontoura BM (2014) Nuclear trafficking in health and disease. Curr Opin Cell Biol 28:28–35. https://doi.org/10.1016/j.ceb.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  115. Franks TM, McCloskey A, Shokirev MN, Benner C, Rathore A, Hetzer MW (2017) Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes Dev 31(22):2222–2234. https://doi.org/10.1101/gad.306753.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rosenblum JS, Blobel G (1999) Autoproteolysis in nucleoporin biogenesis. Proc Natl Acad Sci USA 96(20):11370–11375

    Article  CAS  PubMed  Google Scholar 

  117. Kalverda B, Pickersgill H, Shloma VV, Fornerod M (2010) Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140(3):360–371. https://doi.org/10.1016/j.cell.2010.01.011

    Article  CAS  PubMed  Google Scholar 

  118. Capelson M, Liang Y, Schulte R, Mair W, Wagner U, Hetzer MW (2010) Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140(3):372–383. https://doi.org/10.1016/j.cell.2009.12.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Laurell E, Beck K, Krupina K, Theerthagiri G, Bodenmiller B, Horvath P, Aebersold R, Antonin W, Kutay U (2011) Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry. Cell 144(4):539–550. https://doi.org/10.1016/j.cell.2011.01.012

    Article  CAS  PubMed  Google Scholar 

  120. Laurell E, Kutay U (2011) Dismantling the NPC permeability barrier at the onset of mitosis. Cell Cycle 10(14):2243–2245

    Article  CAS  PubMed  Google Scholar 

  121. Stuwe T, von Borzyskowski LS, Davenport AM, Hoelz A (2012) Molecular basis for the anchoring of proto-oncoprotein Nup98 to the cytoplasmic face of the nuclear pore complex. J Mol Biol 419(5):330–346. https://doi.org/10.1016/j.jmb.2012.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Enninga J, Levy DE, Blobel G, Fontoura BM (2002) Role of nucleoporin induction in releasing an mRNA nuclear export block. Science 295(5559):1523–1525

    Article  CAS  PubMed  Google Scholar 

  123. Champion L, Linder MI, Kutay U (2017) Cellular Reorganization during Mitotic Entry. Trends Cell Biol 27(1):26–41. https://doi.org/10.1016/j.tcb.2016.07.004

    Article  PubMed  Google Scholar 

  124. Linder MI, Kohler M, Boersema P, Weberruss M, Wandke C, Marino J, Ashiono C, Picotti P, Antonin W, Kutay U (2017) Mitotic disassembly of nuclear pore complexes involves CDK1- and PLK1-Mediated phosphorylation of key interconnecting nucleoporins. Dev Cell 43(2):141–156. https://doi.org/10.1016/j.devcel.2017.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Blethrow JD, Glavy JS, Morgan DO, Shokat KM (2008) Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc Natl Acad Sci USA 105(5):1442–1447. https://doi.org/10.1073/pnas.0708966105

    Article  PubMed  Google Scholar 

  126. De Souza CP, Osmani SA (2007) Mitosis, not just open or closed. Eukaryot Cell 6(9):1521–1527. https://doi.org/10.1128/EC.00178-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. De Souza CP, Horn KP, Masker K, Osmani SA (2003) The SONB(NUP98) nucleoporin interacts with the NIMA kinase in Aspergillus nidulans. Genetics 165(3):1071–1081

    PubMed  PubMed Central  Google Scholar 

  128. De Souza CP, Hashmi SB, Horn KP, Osmani SA (2006) A point mutation in the Aspergillus nidulans sonBNup98 nuclear pore complex gene causes conditional DNA damage sensitivity. Genetics 174(4):1881–1893. https://doi.org/10.1534/genetics.106.063438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jeganathan KB, Malureanu L, van Deursen JM (2005) The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438(7070):1036–1039. https://doi.org/10.1038/nature04221

    Article  CAS  PubMed  Google Scholar 

  130. von Kobbe C, van Deursen JM, Rodrigues JP, Sitterlin D, Bachi A, Wu X, Wilm M, Carmo-Fonseca M, Izaurralde E (2000) Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98. Mol Cell 6(5):1243–1252

    Article  Google Scholar 

  131. Panda D, Pascual-Garcia P, Dunagin M, Tudor M, Hopkins KC, Xu J, Gold B, Raj A, Capelson M, Cherry S (2014) Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila. Proc Natl Acad Sci USA 111(37):E3890–E3899. https://doi.org/10.1073/pnas.1410087111

    Article  CAS  PubMed  Google Scholar 

  132. Singer S, Zhao R, Barsotti AM, Ouwehand A, Fazollahi M, Coutavas E, Breuhahn K, Neumann O, Longerich T, Pusterla T, Powers MA, Giles KM, Leedman PJ, Hess J, Grunwald D, Bussemaker HJ, Singer RH, Schirmacher P, Prives C (2012) Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes. Mol Cell 48(5):799–810. https://doi.org/10.1016/j.molcel.2012.09.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Faria AM, Levay A, Wang Y, Kamphorst AO, Rosa ML, Nussenzveig DR, Balkan W, Chook YM, Levy DE, Fontoura BM (2006) The nucleoporin Nup96 is required for proper expression of interferon-regulated proteins and functions. Immunity 24(3):295–304. https://doi.org/10.1016/j.immuni.2006.01.014

    Article  CAS  PubMed  Google Scholar 

  134. Gough SM, Slape CI, Aplan PD (2011) NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 118(24):6247–6257. https://doi.org/10.1182/blood-2011-07-328880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cohen M, Feinstein N, Wilson KL, Gruenbaum Y (2003) Nuclear pore protein gp210 is essential for viability in HeLa cells and Caenorhabditis elegans. Mol Biol Cell 14(10):4230–4237. https://doi.org/10.1091/mbc.e03-04-0260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kupke T, Malsam J, Schiebel E (2017) A ternary membrane protein complex anchors the spindle pole body in the nuclear envelope in budding yeast. J Biol Chem 292(20):8447–8458. https://doi.org/10.1074/jbc.M117.780601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mansfeld J, Guttinger S, Hawryluk-Gara LA, Pante N, Mall M, Galy V, Haselmann U, Muhlhausser P, Wozniak RW, Mattaj IW, Kutay U, Antonin W (2006) The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells. Mol Cell 22(1):93–103. https://doi.org/10.1016/j.molcel.2006.02.015

    Article  CAS  PubMed  Google Scholar 

  138. Antonin W, Mattaj IW (2005) Nuclear pore complexes: round the bend? Nat Cell Biol 7(1):10–12

    Article  CAS  PubMed  Google Scholar 

  139. Stavru F, Hulsmann BB, Spang A, Hartmann E, Cordes VC, Gorlich D (2006) NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes. J Cell Biol 173(4):509–519. https://doi.org/10.1083/jcb.200601001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Onischenko E, Stanton LH, Madrid AS, Kieselbach T, Weis K (2009) Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance. J Cell Biol 185(3):475–491. https://doi.org/10.1083/jcb.200810030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chadrin A, Hess B, San Roman M, Gatti X, Lombard B, Loew D, Barral Y, Palancade B, Doye V (2010) Pom33, a novel transmembrane nucleoporin required for proper nuclear pore complex distribution. J Cell Biol 189(5):795–811. https://doi.org/10.1083/jcb.200910043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Floch AG, Tareste D, Fuchs PF, Chadrin A, Naciri I, Leger T, Schlenstedt G, Palancade B, Doye V (2015) Nuclear pore targeting of the yeast Pom33 nucleoporin depends on karyopherin and lipid binding. J Cell Sci 128(2):305–316. https://doi.org/10.1242/jcs.158915

    Article  CAS  PubMed  Google Scholar 

  143. Mosalaganti S, Kosinski J, Albert S, Schaffer M, Strenkert D, Salome PA, Merchant SS, Plitzko JM, Baumeister W, Engel BD, Beck M (2018) In situ architecture of the algal nuclear pore complex. Nat Commun 9:2361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Weis K (2002) Nucleocytoplasmic transport: cargo trafficking across the border. Curr Opin Cell Biol 14(3):328–335

    Article  CAS  PubMed  Google Scholar 

  145. Bonner WM (1975) Protein migration into nuclei. II. Frog oocyte nuclei accumulate a class of microinjected oocyte nuclear proteins and exclude a class of microinjected oocyte cytoplasmic proteins. J Cell Biol 64(2):431–437. https://doi.org/10.1083/jcb.64.2.431

    Article  CAS  PubMed  Google Scholar 

  146. Bonner WM (1975) Protein migration into nuclei. I. Frog oocyte nuclei in vivo accumulate microinjected histones, allow entry to small proteins, and exclude large proteins. J Cell Biol 64(2):421–430. https://doi.org/10.1083/jcb.64.2.421

    Article  CAS  PubMed  Google Scholar 

  147. Stewart M (2007) Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol 8(3):195–208. https://doi.org/10.1038/nrm2114

    Article  CAS  PubMed  Google Scholar 

  148. Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (2007) Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem 282(8):5101–5105. https://doi.org/10.1074/jbc.R600026200

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Much thanks goes to Thomas Cattabiani for critical reading and helpful discussions. The author is funded by NIH R15 GM119118-02. The author is grateful to Grace Glavy, Michelle A. Veronin, Benjamin R. Jordan and Khanh Huy Bui for their contributions. And Günter Blobel for his influence.

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Glavy, J.S. The Quest for the Blueprint of the Nuclear Pore Complex. Protein J 38, 363–376 (2019). https://doi.org/10.1007/s10930-019-09858-z

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