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: 33.61). 04/2007; 315(5819):1729-32. DOI: 10.1126/science.1135730
Source: PubMed


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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    • "Our dimerized Nup84 complex can easily fit into this model, which would lead to a ring-like assembly resembling the repetitive element of a chain-link fence (Figure S3). The repetitive occurrence of stable associations between two Nup84 complexes followed by long flexible stalks (Nup145C-Nup84-Nup133) forming the fence-like network could combine two important features: (1) the necessary rigidity of a putative coat for stabilizing curvature of the nuclear envelope at the sites of NPCs, which is a discussed role of the Nup84 complex in the NPC (Debler et al., 2010; Leksa and Schwartz, 2010), and (2) an important degree of flexibility allowing, for example, dilatation of the nuclear pore diameter during translocation of large cargos (Melcá k et al., 2007; Solmaz et al., 2011). "
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    ABSTRACT: A key building block of the nuclear pore complex (NPC) is the Nup84 subcomplex that has been structurally analyzed predominantly in the yeast system. To expand this analysis and gain insight into the evolutionary conservation of its structure, we reconstituted an octameric Nup84 complex using the subunits from a thermophile, Chaetomium thermophilum (ct). This assembly carries Nup37 and Elys, which are characteristic subunits of the orthologous human Nup107-Nup160 complex but absent from the yeast Saccharomyces cerevisiae. We found that Elys binds cooperatively to the complex requiring both Nup37 and Nup120. Unexpectedly, the reconstituted ctNup84 complex formed a striking dimer structure with an unpredicted side-to-side arrangement of two molecules. Finally, crosslinking mass spectrometry allowed the mapping of key protein interfaces within the Y-shaped complex. Thus, the thermophilic Nup84 complex can serve as a structural model for higher eukaryotic Nup107-Nup160 assemblies to gain insight into its possible configuration within the NPC scaffold.
    No preview · Article · Aug 2013 · Structure
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    • "Later, Nup54, Nup58 and Nup62 were found to coprecipitate in a complex from rat and Xenopus protein nuclear extracts [57]. More recently, the crystal structures of the interacting domains of Rattus norvegicus Nup54, Nup58 and Nup62 were determined, indicating that as many as 224 copies of these proteins form a flexible transport channel with a ring diameter that can be modulated by circumferential sliding induced by interactions with transport receptors [58], [59]. "
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    ABSTRACT: The selective trafficking of proteins and RNAs through the nuclear envelope regulates nuclear-cytoplasmic segregation of macromolecules and is mediated by nucleopore complexes (NPCs), which consist of about 400 nucleoporins (Nups) of about 30 types. Extensive studies of nucleoporin function in yeast and vertebrates showed that Nups function in nucleocytoplasmic trafficking and other processes. However, limited studies of plant Nups have identified only a few mutations, which cause pleiotropic phenotypes including reduced growth and early flowering. Here, we describe loss-of-function alleles of Arabidopsis TRANSCURVATA1 (TCU1); these mutations cause increased hypocotyl and petiole length, reticulate and asymmetrically epinastic leaf laminae of reduced size, and early flowering. TCU1 is transcribed in all of the organs and tissues examined, and encodes the putative ortholog of yeast and vertebrate Nup58, a nucleoporin of the Nup62 subcomplex. Nup58 forms the central channel of the NPC and acts directly in translocation of proteins through the nuclear envelope in yeast and vertebrates. Yeast two-hybrid (Y2H) assays identified physical interactions between TCU1/NUP58 and 34 proteins, including nucleoporins, SCF (Skp1/Cul1/F-box) ubiquitin ligase complex components and other nucleoplasm proteins. Genetic interactions were also found between TCU1 and genes encoding nucleoporins, soluble nuclear transport receptors and components of the ubiquitin-proteasome and auxin signaling pathways. These genetic and physical interactions indicate that TCU1/NUP58 is a member of the Nup62 subcomplex of the Arabidopsis NPC. Our findings also suggest regulatory roles for TCU1/NUP58 beyond its function in nucleocytoplasmic trafficking, a hypothesis that is supported by the Y2H and genetic interactions that we observed.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Nup192: Structure, Dynamics, Evolution, and Function Such flexibility in the NPC has been suggested by prior highresolution EM studies (Akey, 1995; Yang et al., 1998). Second, this flexibility may be required during the biogenesis of NPC in order to interlock various nucleoporins (Melcá k et al., 2007; Solmaz et al., 2011). Nup192 is known to form multiple interactions with other Nups (Alber et al., 2007a, 2007b; Amlacher et al., 2011), and it has been suggested that it can wrap around the linker-Nup Nic96 (Amlacher et al., 2011). "
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    ABSTRACT: The nuclear pore complex, composed of proteins termed nucleoporins (Nups), is responsible for nucleocytoplasmic transport in eukaryotes. Nuclear pore complexes (NPCs) form an annular structure composed of the nuclear ring, cytoplasmic ring, a membrane ring, and two inner rings. Nup192 is a major component of the NPC's inner ring. We report the crystal structure of Saccharomyces cerevisiae Nup192 residues 2-960 [ScNup192(2-960)], which adopts an α-helical fold with three domains (i.e., D1, D2, and D3). Small angle X-ray scattering and electron microscopy (EM) studies reveal that ScNup192(2-960) could undergo long-range transition between "open" and "closed" conformations. We obtained a structural model of full-length ScNup192 based on EM, the structure of ScNup192(2-960), and homology modeling. Evolutionary analyses using the ScNup192(2-960) structure suggest that NPCs and vesicle-coating complexes are descended from a common membrane-coating ancestral complex. We show that suppression of Nup192 expression leads to compromised nuclear transport and hypothesize a role for Nup192 in modulating the permeability of the NPC central channel.
    Full-text · Article · Mar 2013 · Structure
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