Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles

Trends in Biochemical Sciences

Volumn 41, Issue 1, 2016, Pages 46-61

  Schmidt, H Broder ^a   Görlich, Dirk ^b  

^a STANFORD UNIVERSITY   (United States)

^b MAX PLANCK INSTITUTE FOR BIOPHYSICAL CHEMISTRY   (Germany)

Author keywords

FG domains; Intracellular phase separation; Intrinsically disordered proteins; Nuclear pore; Protein disorder; Protein phases

Indexed keywords

FG PROTEIN; NUCLEAR PROTEIN; NUCLEOPORIN; UNCLASSIFIED DRUG;

BINDING AFFINITY; BINDING SITE; CELL MIGRATION; CELL ORGANELLE; HUMAN; MEMBRANELESS ORGANELLE; NONHUMAN; NUCLEAR PORE COMPLEX; NUCLEOCYTOPLASMIC TRANSPORT; PERMEABILITY BARRIER; PHASE SEPARATION; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DETERMINATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; PROTEIN TRANSPORT; REVIEW; ACTIVE TRANSPORT; ANIMAL; CELL NUCLEUS; METABOLISM; NUCLEAR PORE;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; CELL NUCLEUS; HUMANS; NUCLEAR PORE; ORGANELLES;

EID: 84951794735     PISSN: 09680004     EISSN: 13624326     Source Type: Journal    
DOI: 10.1016/j.tibs.2015.11.001     Document Type: Review

References (133)

1. Watson M.L. Pores in the mammalian nuclear membrane. Biochim. Biophys. Acta 1954, 15:475-479.
2. Stevens B.J., Swift H. RNA transport from nucleus to cytoplasm in Chironomus salivary glands. J. Cell Biol. 1966, 31:55-77.
3. Moore M., Blobel G. The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature 1993, 365:661-663.
4. Melchior F., et al. Inhibition of nuclear protein import by nonhydrolyzable analogs of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor. J. Cell Biol. 1993, 123:1649-1659.
5. Bischoff F.R., Ponstingl H. Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 1991, 354:80-82.
6. Bischoff F., et al. RanGAP1 induces GTPase activity of nuclear ras-related Ran. Proc. Natl. Acad. Sci. U.S.A. 1994, 91:2587-2591.
7. Görlich D., et al. Isolation of a protein that is essential for the first step of nuclear protein import. Cell 1994, 79:767-778.
8. Görlich D., et al. Distinct functions for the two importin subunits in nuclear protein import. Nature 1995, 377:246-248.
9. Imamoto N., et al. The nuclear pore-targeting complex binds to nuclear pores after association with a karyophile. FEBS Lett. 1995, 368:415-419.
10. Chi N.C., et al. Sequence and characterization of cytoplasmic nuclear protein import factor p97. J. Cell Biol. 1995, 130:265-274.
11. Davis L.I., Blobel G. Identification and characterization of a nuclear pore complex protein. Cell 1986, 45:699-709.
12. Hurt E.C. A novel nucleoskeletal-like protein located at the nuclear periphery is required for the life cycle of Saccharomyces cerevisiae. EMBO J. 1988, 7:4323-4334.
13. Cronshaw J.M., et al. Proteomic analysis of the mammalian nuclear pore complex. J. Cell Biol. 2002, 158:915-927.
14. Rout M.P., et al. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J. Cell Biol. 2000, 148:635-651.
15. Strawn L.A., et al. Minimal nuclear pore complexes define FG repeat domains essential for transport. Nat. Cell Biol. 2004, 6:197-206.
16. Wente S.R., et al. A new family of yeast nuclear pore complex proteins. J. Cell Biol. 1992, 119:705-723.
17. Yamada J., et al. A bimodal distribution of two distinct categories of intrinsically disordered structures with separate functions in FG nucleoporins. Mol. Cell. Proteomics 2010, 9:2205-2224.
18. Bui K.H., et al. Integrated structural analysis of the human nuclear pore complex scaffold. Cell 2013, 155:1233-1243.
19. Maimon T., et al. The human nuclear pore complex as revealed by cryo-electron tomography. Structure 2012, 20:998-1006.
20. Eibauer M., et al. Structure and gating of the nuclear pore complex. Nat. Commun. 2015, 6:7532.
21. Belgareh N., et al. An evolutionarily conserved NPC subcomplex, which redistributes in part to kinetochores in mammalian cells. J. Cell Biol. 2001, 154:1147-1160.
22. Lutzmann M., et al. Modular self-assembly of a Y-shaped multiprotein complex from seven nucleoporins. EMBO J. 2002, 21:387-397.
23. Maul G.G. Nuclear pore complexes. Elimination and reconstruction during mitosis. J. Cell Biol. 1977, 74:492-500.
24. Bonner W.M. 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. 1975, 64:421-430.
25. Mohr D., et al. Characterisation of the passive permeability barrier of nuclear pore complexes. EMBO J. 2009, 28:2541-2553.
26. Cook A., et al. Structural biology of nucleocytoplasmic transport. Annu. Rev. Biochem. 2007, 76:647-671.
27. Güttler T., Görlich D. Ran-dependent nuclear export mediators: a structural perspective. EMBO J. 2011, 30:3457-3474.
28. Sloan K.E., et al. Nucleocytoplasmic transport of RNAs and RNA-protein complexes. J. Mol. Biol. 2015, Published online October 3, 2015. 10.1016/j.jmb.2015.09.023.
29. Görlich D., Kutay U. Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol. 1999, 15:607-660.
30. Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell 2003, 112:441-451.
31. Izaurralde E., et al. The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. EMBO J. 1997, 16:6535-6547.
32. Görlich D., et al. Characterization of Ran-driven cargo transport and the RanGTPase system by kinetic measurements and computer simulation. EMBO J. 2003, 22:1088-1100.
33. Kalab P., et al. Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 2002, 295:2452-2456.
34. Rexach M., Blobel G. Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins. Cell 1995, 83:683-692.
35. Kutay U., et al. Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 1997, 90:1061-1071.
36. Fornerod M., et al. Crm1 is an export receptor for leucine rich nuclear export signals. Cell 1997, 90:1051-1060.
37. Bayliss R., et al. Interaction between NTF2 and xFxFG-containing nucleoporins is required to mediate nuclear import of RanGDP. J. Mol. Biol. 1999, 293:579-593.
38. Bednenko J., et al. Importin beta contains a COOH-terminal nucleoporin binding region important for nuclear transport. J. Cell Biol. 2003, 162:391-401.
39. Chaillan-Huntington C., et al. Dissecting the interactions between NTF2, RanGDP, and the nucleoporin XFXFG repeats. J. Biol. Chem. 2000, 275:5874-5879.
40. Iovine M.K., et al. The GLFG repetitive region of the nucleoporin Nup116p interacts with Kap95p, an essential yeast nuclear import factor. J. Cell Biol. 1995, 131:1699-1713.
41. Denning D.P., et al. Disorder in the nuclear pore complex: the FG repeat regions of nucleoporins are natively unfolded. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:2450-2455.
42. Frey S., Görlich D. A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell 2007, 130:512-523.
43. Hülsmann B.B., et al. The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell 2012, 150:738-751.
44. Patel S.S., et al. Natively unfolded nucleoporins gate protein diffusion across the nuclear pore complex. Cell 2007, 129:83-96.
45. Ribbeck K., Görlich D. The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion. EMBO J. 2002, 21:2664-2671.
46. Schmidt H.B., Görlich D. Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. Elife 2015, 4.
47. Ori A., et al. Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines. Mol. Syst. Biol. 2013, 9:648.
48. Denning D.P., Rexach M.F. Rapid evolution exposes the boundaries of domain structure and function in natively unfolded FG nucleoporins. Mol. Cell. Proteomics 2007, 6:272-282.
49. Park N., et al. Differential targeting of nuclear pore complex proteins in poliovirus-infected cells. J. Virol. 2008, 82:1647-1655.
50. Paschal B.M., Gerace L. Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62. J. Cell Biol. 1995, 129:925-937.
51. Radu A., et al. The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex. Cell 1995, 81:215-222.
52. Frey S., et al. FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. Science 2006, 314:815-817.
53. Morrison J., et al. Solution NMR study of the interaction between NTF2 and nucleoporin FxFG repeats. J. Mol. Biol. 2003, 333:587-603.
54. Isgro T.A., Schulten K. Binding dynamics of isolated nucleoporin repeat regions to importin-beta. Structure 2005, 13:1869-1879.
55. Port S.A., et al. Structural and functional characterization of CRM1-Nup214 interactions reveals multiple FG-binding sites Involved in nuclear export. Cell Rep. 2015, 13:690-702.
56. Ribbeck K., Görlich D. Kinetic analysis of translocation through nuclear pore complexes. EMBO J. 2001, 20:1320-1330.
57. Hahn S., Schlenstedt G. Importin β-type nuclear transport receptors have distinct binding affinities for Ran-GTP. Biochem. Biophys. Res. Commun. 2011, 406:383-388.
58. Yang W., Musser S.M. Nuclear import time and transport efficiency depend on importin beta concentration. J. Cell Biol. 2006, 174:951-961.
59. Frey S., Görlich D. FG/FxFG as well as GLFG repeats form a selective permeability barrier with self-healing properties. EMBO J. 2009, 28:2554-2567.
60. Lowe A.R., et al. Importin-β modulates the permeability of the nuclear pore complex in a Ran-dependent manner. Elife 2015, 4:e04052.
61. Andersen K.R., et al. Scaffold nucleoporins Nup188 and Nup192 share structural and functional properties with nuclear transport receptors. Elife 2013, 2:e00745.
62. Schrader N., et al. Structural basis of the nic96 subcomplex organization in the nuclear pore channel. Mol. Cell 2008, 29:46-55.
63. Xu S., Powers M.A. In vivo analysis of human nucleoporin repeat domain interactions. Mol. Biol. Cell 2013, 24:1222-1231.
64. Ader C., et al. Amyloid-like interactions within nucleoporin FG hydrogels. Proc. Natl. Acad. Sci. U.S.A. 2010, 107:6281-6285.
65. Milles S., Lemke E.A. Single molecule study of the intrinsically disordered FG-repeat nucleoporin 153. Biophys. J. 2011, 101:1710-1719.
66. Labokha A.A., et al. Systematic analysis of barrier-forming FG hydrogels from Xenopus nuclear pore complexes. EMBO J. 2013, 32:204-218.
67. Rout M.P., et al. Virtual gating and nuclear transport: the hole picture. Trends Cell Biol. 2003, 13:622-628.
68. Piehler J., et al. A high-density poly(ethylene glycol) polymer brush for immobilization on glass-type surfaces. Biosens. Bioelectron. 2000, 15:473-481.
69. Zhou H-X. Loops in proteins can be modeled as worm-like chains. J. Phys. Chem. B 2001, 105:6763-6766.
70. Lim R.Y., et al. Nanomechanical basis of selective gating by the nuclear pore complex. Science 2007, 318:640-643.
71. Kapinos L.E., et al. Karyopherin-centric control of nuclear pores based on molecular occupancy and kinetic analysis of multivalent binding with FG nucleoporins. Biophys. J. 2014, 106:1751-1762.
72. Jovanovic-Talisman T., et al. Artificial nanopores that mimic the transport selectivity of the nuclear pore complex. Nature 2009, 457:1023-1027.
73. Melcak I., et al. Structure of Nup58/45 suggests flexible nuclear pore diameter by intermolecular sliding. Science 2007, 315:1729-1732.
74. Solmaz S.R., et al. Ring cycle for dilating and constricting the nuclear pore. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:5858-5863.
75. Ulrich A., et al. The stoichiometry of the nucleoporin 62 subcomplex of the nuclear pore in solution. Mol. Biol. Cell 2014, 25:1484-1492.
76. Chug H., et al. Crystal structure of the metazoan Nup62•Nup58•Nup54 nucleoporin complex. Science 2015, 350:106-110.
77. Stuwe T., et al. Architecture of the fungal nuclear pore inner ring complex. Science 2015, 350:56-64.
78. Eisele N.B., et al. Ultrathin nucleoporin phenylalanine-glycine repeat films and their interaction with nuclear transport receptors. EMBO Rep. 2010, 11:366-372.
79. Eisele N.B., et al. Cohesiveness tunes assembly and morphology of FG nucleoporin domain meshworks - implications for nuclear pore permeability. Biophys. J. 2013, 105:1860-1870.
80. Bestembayeva A., et al. Nanoscale stiffness topography reveals structure and mechanics of the transport barrier in intact nuclear pore complexes. Nat. Nanotechnol. 2015, 10:60-64.
81. Milles S., et al. Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors. Cell 2015, 163:734-745.
82. Yang W., et al. Imaging of single-molecule translocation through nuclear pore complexes. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:12887-12892.
83. Kubitscheck U., et al. Nuclear transport of single molecules: dwell times at the nuclear pore complex. J. Cell Biol. 2005, 168:233-243.
84. Powers M.A., et al. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. J. Cell Biol. 1997, 136:241-250.
85. Laurell E., et al. Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry. Cell 2011, 144:539-550.
86. Tu L.C., et al. Large cargo transport by nuclear pores: implications for the spatial organization of FG-nucleoporins. EMBO J. 2013, 32:3220-3230.
87. Uversky V.N., et al. Why are 'natively unfolded' proteins unstructured under physiologic conditions. Proteins 2000, 41:415-427.
88. Monsellier E., Chiti F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO Rep. 2007, 8:737-742.
89. Shulga N., Goldfarb D.S. Binding dynamics of structural nucleoporins govern nuclear pore complex permeability and may mediate channel gating. Mol. Cell. Biol. 2003, 23:534-542.
90. Malinovska L., et al. Protein disorder, prion propensities, and self-organizing macromolecular collectives. Biochim. Biophys. Acta 2013, 1834:918-931.
91. Burke K.A., et al. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 2015, 60:231-241.
92. Elbaum-Garfinkle S., et al. The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. Proc. Natl. Acad. Sci. U.S.A. 2015, 112:7189-7194.
93. Kato M., et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 2012, 149:753-767.
94. Kwon I., et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 2013, 155:1049-1060.
95. Lin Y., et al. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 2015, 60:208-219.
96. Molliex A., et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 2015, 163:123-133.
97. Nott T.J., et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 2015, 57:936-947.
98. Patel A., et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 2015, 162:1066-1077.
99. Updike D., Strome S. P granule assembly and function in Caenorhabditis elegans germ cells. J. Androl. 2010, 31:53-60.
100. Voronina E., et al. RNA granules in germ cells. Cold Spring Harb. Perspect. Biol. 2011, 3:a002774.
101. Updike D.L., et al. P granules extend the nuclear pore complex environment in the C. elegans germ line. J. Cell Biol. 2011, 192:939-948.
102. Voronina E., Seydoux G. The C. elegans homolog of nucleoporin Nup98 is required for the integrity and function of germline P granules. Development 2010, 137:1441-1450.
103. Brangwynne C.P., et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 2009, 324:1729-1732.
104. Wang J.T., et al. Regulation of RNA granule dynamics by phosphorylation of serine-rich, intrinsically disordered proteins in C. elegans. Elife 2014, 3:e04591.
105. Brangwynne C.P., et al. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:4334-4339.
106. Chiti F., Dobson C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 2006, 75:333-366.
107. Ren P.H., et al. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 2009, 11:219-225.
108. Holmqvist S., et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014, 128:805-820.
109. Astbury W.T., et al. The X-ray interpretation of denaturation and the structure of the seed globulins. Biochem. J. 1935, 29:2351-2360.1.
110. Geddes A.J., et al. 'Cross-beta' conformation in proteins. J. Mol. Biol. 1968, 32:343-358.
111. Nelson R., et al. Structure of the cross-beta spine of amyloid-like fibrils. Nature 2005, 435:773-778.
112. Khurana R., et al. Mechanism of thioflavin T binding to amyloid fibrils. J. Struct. Biol. 2005, 151:229-238.
113. Petri M., et al. Structural characterization of nanoscale meshworks within a nucleoporin FG hydrogel. Biomacromolecules 2012, 13:1882-1889.
114. Alberti S., et al. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 2009, 137:146-158.
115. Halfmann R., et al. Prion formation by a yeast GLFG nucleoporin. Prion 2012, 6:391-399.
116. Kroschwald S., et al. Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. Elife 2015, 4.
117. López de la Paz M., Serrano L. Sequence determinants of amyloid fibril formation. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:87-92.
118. Hanover J.A., et al. O-linked N-acetylglucosamine is attached to proteins of the nuclear pore. Evidence for cytoplasmic and nucleoplasmic glycoproteins. J. Biol. Chem. 1987, 262:9887-9894.
119. Park M.K., et al. A monoclonal antibody against a family of nuclear pore proteins (nucleoporins): O-linked N-acetylglucosamine is part of the immunodeterminant. Proc. Natl. Acad. Sci. U.S.A. 1987, 84:6462-6466.
120. Holt G.D., et al. Nuclear pore complex glycoproteins contain cytoplasmically disposed O-linked N-acetylglucosamine. J. Cell Biol. 1987, 104:1157-1164.
121. Finlay D.R., et al. Inhibition of in vitro nuclear transport by a lectin that binds to nuclear pores. J. Cell Biol. 1987, 104:189-200.
122. Zhu Y., et al. Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. J. Mol. Cell Biol. 2015.
123. Pante N., Kann M. Nuclear pore complex is able to transport macromolecules with diameters of ~39nm. Mol. Biol. Cell 2002, 13:425-434.
124. Ho J.H., et al. Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit. J. Cell Biol. 2000, 151:1057-1066.
125. Yao W., et al. Nuclear export of ribosomal 60S subunits by the general mRNA export receptor Mex67-Mtr2. Mol. Cell 2007, 26:51-62.
126. Wild T., et al. A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS Biol. 2010, 8:e1000522.
127. Englmeier L., et al. Receptor-mediated substrate translocation through the nuclear pore complex without nucleotide triphosphate hydrolysis. Curr. Biol. 1999, 9:30-41.
128. Ribbeck K., et al. The translocation of transportin-cargo complexes through nuclear pores is independent of both Ran and energy. Curr. Biol. 1999, 9:47-50.
129. Schwoebel E.D., et al. Ran-dependent signal-mediated nuclear import does not require GTP hydrolysis by Ran. J. Biol. Chem. 1998, 273:35170-35175.
130. Weis K., et al. Characterization of the nuclear protein import mechanism using Ran mutants with altered nucleotide binding specificities. EMBO J. 1996, 15:7120-7128.
131. Sickmeier M., et al. DisProt: the Database of Disordered Proteins. Nucleic Acids Res. 2007, 35:D786-D793.
132. Bernstein F.C., et al. The Protein Data Bank: a computer-based archival file for macromolecular structures. Arch. Biochem. Biophys. 1978, 185:584-591.
133. Hyman A.A., et al. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 2014, 30:39-58.