Structure of Nup58/45 Suggests Flexible Nuclear Pore Diameter by Intermolecular Sliding

Laboratory of Cell Biology, Howard Hughes Medical Institute, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Science (Impact Factor: 31.48). 04/2007; 315(5819):1729-32. DOI: 10.1126/science.1135730
Source: PubMed

ABSTRACT The nucleoporins Nup58 and Nup45 are part of the central transport channel of the nuclear pore complex, which is thought to
have a flexible diameter. In the crystal structure of an α-helical region of mammalian Nup58/45, we identified distinct tetramers,
each consisting of two antiparallel hairpin dimers. The intradimeric interface is hydrophobic, whereas dimer-dimer association
occurs through large hydrophilic residues. These residues are laterally displaced in various tetramer conformations, which
suggests an intermolecular sliding by 11 angstroms. We propose that circumferential sliding plays a role in adjusting the
diameter of the central transport channel.

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    • "Eight segments are shown. (C) Cartoon representation of the Nup58 homotetramer (dimers in pink and red) (Melčák et al., 2007). (D) Schematic representation of a Nup54·Nup58 heterooligomer ring. "
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    ABSTRACT: The nuclear pore complex encloses a central channel for nucleocytoplasmic transport, which is thought to consist of three nucleoporins, Nup54, Nup58, and Nup62. However, the structure and composition of the channel are elusive. We determined the crystal structures of the interacting domains between these nucleoporins and pieced together the molecular architecture of the mammalian transport channel. Located in the channel midplane is a flexible Nup54⋅Nup58 ring that can undergo large rearrangements yielding diameter changes from ∼20 to ∼40 nm. Nup62⋅Nup54 triple helices project alternately up and down from either side of the midplane ring and form nucleoplasmic and cytoplasmic entries. The channel consists of as many as 224 copies of the three nucleoporins, amounting to a molar mass of 12.3 MDa and contributing 256 phenylalanine-glycine repeat regions. We propose that the occupancy of these repeat regions with transport receptors modulates ring diameter and transport activity.
    Cell 10/2011; 147(3):590-602. DOI:10.1016/j.cell.2011.09.034 · 33.12 Impact Factor
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    • "The second is the conformational flexibility of both the core constituents and the FG (phenylalanine-glycine) repeat-containing tentacles that fill the nuclear pore. Blobel speculated that the " wobblicity " of the NPC core could allow its diameter to fluctuate and accommodate cargos of varying sizes (Melcak et al., 2007; Nagy et al., 2009). The unstructured, hydrophobic character of the FG-repeat containing Nups, which interact directly with import factors, provides a fluctuating selectivity barrier (a highly dynamic molecular sieve) through which cargo must be escorted and actively transported (Terry and Wente, 2009). "
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    ABSTRACT: A symposium was held at the University of California, San Diego, to honor the contributions of Nobel Laureate, George Palade, to cell biology. The speakers included Günter Blobel, on the structure and function of nuclear pore complexes; Peter Walter, on the unfolded protein response in health and disease; Randy Schekman, on human disease-linked mutations in the COPII machinery; Scott Emr, on the regulation of plasma membrane composition by selective endocytosis; Roger Kornberg, on the structure and function of the transcription machinery; Peter Novick, on the regulation of rab GTPases along the secretory pathway; Jim Spudich, on the mechanism of the enigmatic myosin VI motor; and Joe Goldstein, on the function of the Niemann-Pick C (NPC)-linked gene products, NPC1 and NPC2, in cholesterol transport. Their work showcased the multidisciplinary nature, diversity, and vitality of cell biology. In the words of George Palade, their talks also illustrated "how cell biology could be used to understand disease and how disease could be used to discover normal cell biology." An integrated understanding of the cellular machinery will be essential in tackling the plethora of questions and challenges posed by completion of the human genome and for understanding the molecular mechanisms underlying human disease.
    Molecular biology of the cell 07/2010; 21(14):2367-70. DOI:10.1091/mbc.E10-03-0179 · 5.98 Impact Factor
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    • "In both, the proteins are held together by coiled-coil interactions (Bailer et al., 2001) and the Nsp1-Nup57-Nup49 complex is, in addition, tethered to the NPC scaffold via the N-terminal coiled-coil region of Nic96 (Grandi et al., 1995). So far, only a homodimerized 10 kDa fragment of Nup58 (the vertebrate ortholog to Nup57) has been structurally characterized (Melcak et al., 2007). Biochemical analysis suggests that the network involves specific rather than promiscuous interactions, arguing for a specific tethering function for the coiled-coil segments. "
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    ABSTRACT: Nuclear pore complexes (NPCs) perforate the nuclear envelope and represent the exclusive passageway into and out of the nucleus of the eukaryotic cell. Apart from their essential transport function, components of the NPC have important, direct roles in nuclear organization and in gene regulation. Because of its central role in cell biology, it is of considerable interest to determine the NPC structure at atomic resolution. The complexity of these large, 40-60 MDa protein assemblies has for decades limited such structural studies. More recently, exploiting the intrinsic modularity of the NPC, structural biologists are making progress toward understanding this nanomachine in molecular detail. Structures of building blocks of the stable, architectural scaffold of the NPC have been solved, and distinct models for their assembly proposed. Here we review the status of the field and lay out the challenges and the next steps toward a full understanding of the NPC at atomic resolution.
    Structure 09/2009; 17(9):1156-68. DOI:10.1016/j.str.2009.07.014 · 6.79 Impact Factor
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