Nucleoporin Domain Topology is Linked to the Transport Status of the Nuclear Pore Complex

Paulillo, Sara M.; Phillips, Erica M.; Köser, Joachim; Sauder, Ursula; Ullman, Katharine S.; Powers, Maureen A.; Fahrenkrog, Birthe

doi:10.1016/j.jmb.2005.06.034

Cited by 69 publications

(95 citation statements)

References 52 publications

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“…This mechanism would explain how a cytoplasmic localized nucleoporin can mediate export (33,34). To examine this possibility (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to contributing to the hydrophobic inner core of the NPC (8), the FG-repeat region of Nup214 has recently been proposed to move cargo through the NPC from the nuclear to the cytoplasmic face of the NE (33,34). In fact, the FG-repeat region of Nup214 is able to cross the NPC by itself (56) and is predicted to be unstructured (57) and long enough to cross the NPC from a cytoplasmic anchoring point.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains to be elucidated as to whether and how NPC asymmetry influences transport processes that are initiated on the opposite side of the NPC. Recent studies proposed that the FG-rich domain of the asymmetric nuclear Nup153 and cytoplasmic Nup214 can cross the NPC providing a binding site to transport receptors and escorting transport complexes through the NPC (32)(33)(34). CRM1 mediates the nuclear export of proteins bearing a nuclear export signal (NES) by binding cooperatively with RanGTP (35)(36)(37)(38).…”

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confidence: 99%

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Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Bernad¹,

Engelsma

Sanderson³

et al. 2006

Journal of Biological Chemistry

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The nuclear pore complex (NPC) conducts macromolecular transport to and from the nucleus and provides a kinetic/hydrophobic barrier composed of phenylalanine-glycine (FG) repeats. Nuclear transport is achieved through permeation of this barrier by transport receptors. The transport receptor CRM1 facilitates export of a large variety of cargoes. Export of the preribosomal 60 S subunit follows this pathway through the adaptor protein NMD3. Using RNA interference, we depleted two FG-containing cytoplasmically oriented NPC complexes, Nup214-Nup88 and Nup358, and investigated CRM1-mediated export. A dramatic defect in NMD3-mediated export of preribosomes was found in Nup214-Nup88-depleted cells, whereas only minor export defects were evident in other CRM1 cargoes or upon depletion of Nup358. We show that the large C-terminal FG domain of Nup214 is not accessible to freely diffusing molecules from the nucleus, indicating that it does not conduct 60 S preribosomes through the NPC. Consistently, derivatives of Nup214 lacking the FG-repeat domain rescued the 60 S export defect. We show that the coiled-coil region of Nup214 is sufficient for 60 S nuclear export, coinciding with recruitment of Nup88 to the NPC. Our data indicate that Nup214 plays independent roles in NPC function by participating in the kinetic/ hydrophobic barrier through its FG-rich domain and by enabling NPC gating through association with Nup88.

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“…This mechanism would explain how a cytoplasmic localized nucleoporin can mediate export (33,34). To examine this possibility (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Bernad¹,

Engelsma

Sanderson³

et al. 2006

Journal of Biological Chemistry

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“…Such characteristic behavior is manifested in FG-nucleoporins, which may be vital to achieve the fast transport rates observed with nucleocytoplasmic transport (Ribbeck and Gorlich 2001). More specifically, this includes: (1) exhibiting a high degree of flexibility and mobility Paulillo et al 2005), (2) being able to interact simultaneously with several binding partners , and (3) promoting fast molecular association and dissociation rates (Gilchrist et al 2002). In addition, immuno-EM studies of yeast NPCs reveal that FG-nucleoporins are predominantly located at the two facial peripheries of the NPC (Rout et al 2000).…”

Section: Nucleocytoplasmic Transport Across the Nuclear Pore Complex:mentioning

confidence: 99%

“…In fact, these remarkable ultrastructural data have challenged many researchers in the field-including ourselves-to replicate, scrutinize, and elaborate on these novel views of NPC architecture Akey 1990;Jarnik and Aebi 1991;Goldberg et al 1997;Kiseleva et al 1998;Stoffler et al 2003;Beck et al 2004). Last but not least, Ris' morphological data also had a profound impact on the molecular dissection of NPC structure (Pante and Aebi 1993;Pante et al 1994;Fahrenkrog et al 1998;Rout et al 2000;Paulillo et al 2005).…”

Section: Introductionmentioning

confidence: 99%

From the trap to the basket: getting to the bottom of the nuclear pore complex

2006

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Nuclear pore complexes (NPCs) are large supramolecular assemblies that perforate the doublemembraned nuclear envelope and serve as the sole gateways of molecular exchange between the cytoplasm and the nucleus in interphase cells. Combining novel specimen preparation regimes with innovative use of highresolution scanning electron microscopy, Hans Ris produced in the late eighties stereo images of the NPC with unparalleled clarity and structural detail, thereby setting new standards in the field. Since that time, efforts undertaken to resolve the molecular structure and architecture, and the numerous interactions that occur between NPC proteins (nucleoporins), soluble transport receptors, and the small GTPase Ran, have led to a deeper understanding of the functional role of NPCs in nucleocytoplasmic transport. In spite of these breakthroughs, getting to the bottom of the actual cargo translocation mechanism through the NPC remains elusive and controversial. Here, we review recent insights into NPC function by correlating structural findings with biochemical data. By introducing new experimental and computational results, we reexamine how NPCs can discriminate between receptor-mediated and passive cargo to promote vectorial translocation in a highly regulated manner. Moreover, we comment on the importance and potential benefits of identifying and experimenting with individual key components implicated in the translocation mechanism. We conclude by dwelling on questions that we feel are pertinent to a more rational understanding of the physical aspects governing NPC mechanics. Last but not least, we substantiate these uncertainties by boldly suggesting a new direction in NPC research as a means to verify such novel concepts, for example, a de novo designed 'minimalist' NPC.

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From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Jühlen,

Fahrenkrog

2023

FEBS Letters

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The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

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Nucleoporin Domain Topology is Linked to the Transport Status of the Nuclear Pore Complex

Cited by 69 publications

References 52 publications

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

Nup214-Nup88 Nucleoporin Subcomplex Is Required for CRM1-mediated 60 S Preribosomal Nuclear Export

From the trap to the basket: getting to the bottom of the nuclear pore complex

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

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