Biology and Biophysics of the Nuclear Pore Complex and Its Components

Lim, Roderick Y. H.; Ullman, Katharine S.; Fahrenkrog, Birthe

doi:10.1016/s1937-6448(08)00632-1

Cited by 72 publications

(65 citation statements)

References 245 publications

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“…[3][4][5][6][7] Post-mitotic NPC assembly occurs concomitantly with the formation of NEs around chromatin. 22 It begins in early anaphase, 14,23 with the recruitment of the Nup107-160 scaffold complex to the chromatin.…”

Section: Distinct Assembly Mechanisms Between Post-mitotic Npc Assembmentioning

confidence: 99%

“…1 The number of nuclear pore complexes (NPCs), the channels for macromolecular transport between the cytoplasm and nucleus, also doubles as the cell cycle progresses. [3][4][5][6][7] NPCs are supramolecular complexes, assembled from multiple copies of approximately 30 different proteins, termed nucleoporins (Nups). For the "economical" formation of NPCs during cell proliferation, their expression and formation process needs to be highly controlled.…”

Section: Introductionmentioning

confidence: 99%

“…However, their formation and regulation, especially during interphase with a closed nuclear envelope, remained unclear. [3][4][5][6][7] To address this question, we established novel techniques to study nuclear volume and NPC formation, and investigated how they were regulated during interphase in dividing human cells. 8,9 Our results indicate that Cdks, especially Cdk1 and Cdk2, control NPC formation during interphase.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear size, nuclear pore number and cell cycle

Maeshima

Iino

Hihara

et al. 2011

Nucleus

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In eukaryotic cells, the nucleus is a complex and sophisticated organelle containing genomic DNA and supports essential cellular activities. Its surface contains many nuclear pore complexes (NPCs), channels for macromolecular transport between the cytoplasm and nucleus. It has been observed that the nuclear volume and the number of NPCs almost doubles during interphase in dividing cells, but the coordination of these events with the cell cycle was poorly understood, particularly in mammalian cells. Recently, we demonstrated that cyclin-dependent protein kinases (Cdks) control interphase NPC formation in dividing human cells. Cdks drive the very early step of NPC formation because Cdk inhibition suppressed the generation of "nascent pores," which are considered to be immature NPCs, and disturbed expression and localization of some nucleoporins. Cdk inhibition did not affect nuclear volume, suggesting that these two processes have distinct regulatory mechanisms in the cell cycle. The details of our experimental systems and finding are discussed in more depth. With new findings recently reported, we also discuss possible molecular mechanisms of interphase NPC formation.

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Section: Distinct Assembly Mechanisms Between Post-mitotic Npc Assembmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nuclear size, nuclear pore number and cell cycle

Maeshima

Iino

Hihara

et al. 2011

Nucleus

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“…The NPC allows for passive diffusion of small molecules including sugars, ions, and water, while simultaneously imposing size-dependent exclusion of macromolecules without nuclear transport factor (TF) binding sites, generating unique nuclear and cytoplasmic compartments (3,4). Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore.…”

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confidence: 99%

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Raveh

Karp

Sparks

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

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Nucleocytoplasmic transport is mediated by the interaction of transport factors (TFs) with disordered phenylalanine-glycine (FG) repeats that fill the central channel of the nuclear pore complex (NPC). However, the mechanism by which TFs rapidly diffuse through multiple FG repeats without compromising NPC selectivity is not yet fully understood. In this study, we build on our recent NMR investigations showing that FG repeats are highly dynamic, flexible, and rapidly exchanging among TF interaction sites. We use unbiased long timescale all-atom simulations on the Anton supercomputer, combined with extensive enhanced sampling simulations and NMR experiments, to characterize the thermodynamic and kinetic properties of FG repeats and their interaction with a model transport factor. Both the simulations and experimental data indicate that FG repeats are highly dynamic random coils, lack intrachain interactions, and exhibit significant entropically driven resistance to spatial confinement. We show that the FG motifs reversibly slide in and out of multiple TF interaction sites, transitioning rapidly between a strongly interacting state and a weakly interacting state, rather than undergoing a much slower transition between strongly interacting and completely noninteracting (unbound) states. In the weakly interacting state, FG motifs can be more easily displaced by other competing FG motifs, providing a simple mechanism for rapid exchange of TF/FG motif contacts during transport. This slide-and-exchange mechanism highlights the direct role of the disorder within FG repeats in nucleocytoplasmic transport, and resolves the apparent conflict between the selectivity and speed of transport.nuclear pore | molecular dynamics | nucleoporins | transport factors | NMR T he nuclear pore complex (NPC) regulates macromolecular transport between the nucleus and the cytoplasm in all eukaryotic cells (1, 2). The NPC allows for passive diffusion of small molecules including sugars, ions, and water, while simultaneously imposing size-dependent exclusion of macromolecules without nuclear transport factor (TF) binding sites, generating unique nuclear and cytoplasmic compartments (3, 4). Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore. In pathological conditions, including many cancers and viral infections, the NPC is hijacked and used to transport undesired particles, or it is modified to attenuate the cellular responses to disease onset (5, 6).TFs traverse the NPC by selective and reversible association with disordered phenylalanine-glycine (FG) repeat domains of the FG nucleoporin proteins (FG Nups), which line the surface of the NPC (7-14). Each FG repeat domain consists of 5-50 FG repeats. In turn, each FG repeat consists of a single FG motif of various sequence flavors, such as the FSFG and GLFG motifs, and 10-30 spacer residues that separate consecutive FG motifs (15, 16). The spacer residues are strongly hydrophilic (17) and rich ...

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“…The passage of molecules into the nucleus occurs through the nuclear pore complexes (NPCs) 6 (10). Nucleocytoplasmic transport is driven by a series of protein-protein interactions and involves several soluble carriers named ␤-karyopherins.…”

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confidence: 99%

Importin-β Is a GDP-to-GTP Exchange Factor of Ran

Lonhienne

Forwood

Marfori

et al. 2009

Journal of Biological Chemistry

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Ran-GTP interacts strongly with importin-␤, and this interaction promotes the release of the importin-␣-nuclear localization signal cargo from importin-␤. Ran-GDP also interacts with importin-␤, but this interaction is 4 orders of magnitude weaker than the Ran-GTP⅐importin-␤ interaction. Here we use the yeast complement of nuclear import proteins to show that the interaction between Ran-GDP and importin-␤ promotes the dissociation of GDP from Ran. The release of GDP from the Ran-GDP-importin-␤ complex stabilizes the complex, which cannot be dissociated by importin-␣. Although Ran has a higher affinity for GDP compared with GTP, Ran in complex with importin-␤ has a higher affinity for GTP. This feature is responsible for the generation of Ran-GTP from Ran-GDP by importin-␤. Ran-binding protein-1 (RanBP1) activates this reaction by forming a trimeric complex with Ran-GDP and importin-␤. Importin-␣ inhibits the GDP exchange reaction by sequestering importin-␤, whereas RanBP1 restores the GDP nucleotide exchange by importin-␤ by forming a tetrameric complex with importin-␤, Ran, and importin-␣. The exchange is also inhibited by nuclear-transport factor-2 (NTF2). We suggest a mechanism for nuclear import, additional to the established RCC1 (Ran-guanine exchange factor)-dependent pathway that incorporates these results.Ran (Gsp1p in yeast) is a Ras-like GTPase that regulates diverse cellular processes, including nuclear transport, mitotic spindle assembly, and post-mitotic nuclear assembly (1, 2). Like other GTPases, Ran can bind GTP and GDP. Ran-GTP is generated in the nucleus by the guanine exchange factor RCC1 (regulator of chromosome condensation 1), which is associated with the chromatin (3). Ran-GDP is produced in the cytoplasm by the activation of the intrinsic GTPase activity of Ran by Ran-GAP1 (GTPase-activating protein) (4) and RanBP1 (Ran-binding protein-1, Yrb1p in yeast). The compartmentalization of RanGAP1 (cytoplasm) and RCC1 (nucleus) gives rise to the asymmetric distribution of Ran-GDP (cytoplasm) and Ran-GTP (nucleus) across the nuclear envelope. This asymmetric distribution of Ran-GDP and Ran-GTP plays a central role in nucleocytoplasmic transport by mediating assembly and disassembly of import and export complexes through interaction with the nuclear import machinery (for reviews, see Refs. 5-9).The passage of molecules into the nucleus occurs through the nuclear pore complexes (NPCs) 6 (10). Nucleocytoplasmic transport is driven by a series of protein-protein interactions and involves several soluble carriers named ␤-karyopherins. Import carriers are called importins and export carriers are called exportins. The classical nuclear import pathway involves importin-␤ (Kap95p in yeast) and the adaptor protein importin-␣ (Kap60p in yeast). In the cytoplasm importin-␤ binds to importin-␣. Their interaction triggers a conformational change of importin-␣ that increases its affinity for cargo proteins containing a nuclear localization signal (NLS) (11,12). The translocation of the resulting complex (import...

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Biology and Biophysics of the Nuclear Pore Complex and Its Components

Cited by 72 publications

References 245 publications

Nuclear size, nuclear pore number and cell cycle

Nuclear size, nuclear pore number and cell cycle

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Importin-β Is a GDP-to-GTP Exchange Factor of Ran

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