Article

Molecular Architecture of the Transport Channel of the Nuclear Pore Complex

Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell (Impact Factor: 33.12). 10/2011; 147(3):590-602. DOI: 10.1016/j.cell.2011.09.034
Source: PubMed

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.

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    • "Indeed, we note that O-GlcNAc is found on over 18 Nups but is most abundant on peripheral Nups (Supplementary Figure S8 and Table S1). O-GlcNAc on Nups is predominantly observed in regions that are not structurally defined except for Nup62, where residue T376 is in an a-helical domain (Solmaz et al., 2011), and Nup98, where residue T184 has been noted in a b-sheet structure (Ren et al., 2010). Accordingly, lower "
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    ABSTRACT: O-glycosylation of the nuclear pore complex (NPC) by O-linked N-acetylglucosamine (O-GlcNAc) is conserved within metazoans. Many nucleoporins (Nups) comprising the NPC are constitutively O-GlcNAcylated, but the functional role of this modification remains enigmatic. We show that loss of O-GlcNAc, induced by either inhibition of O-GlcNAc transferase (OGT) or deletion of the gene encoding OGT, leads to decreased cellular levels of a number of natively O-GlcNAcylated Nups. Loss of O-GlcNAc enables increased ubiquitination of these Nups and their increased proteasomal degradation. The decreased half-life of these deglycosylated Nups manifests in their gradual loss from the NPC and a downstream malfunction of the nuclear pore selective permeability barrier in both dividing and post-mitotic cells. These findings define a critical role of O-GlcNAc modification of the NPC in maintaining its composition and the function of the selectivity filter. The results implicate NPC glycosylation as a regulator of NPC function and reveal the role of conserved glycosylation of the NPC among metazoans. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
    Journal of Molecular Cell Biology 06/2015; DOI:10.1093/jmcb/mjv033 · 8.43 Impact Factor
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    • "It remains to be determined how these truncated proteins specifically impact nuclear transport in Arabidopsis. A structural analysis of the rat NUP62 subcomplex indicates that NUP54 individually binds both NUP62 and NUP58 to form the intact NUP62 complex (Solmaz et al., 2011). These authors show that NUP62 and NUP54 interact by their N-terminal domains, so it is feasible that the truncated NUP62 and NUP54 proteins are still able to make this interaction in Arabidopsis. "
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    Journal of Experimental Botany 08/2014; 65(20). DOI:10.1093/jxb/eru346 · 5.79 Impact Factor
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    • "Within the central channel, less delineate electron optical density with an inner diameter of 27 nm is apparent at lower isosurface threshold levels, which most probably accounts for flexible elements (Figures 2B and 2C). These observations are consistent with the previously reported size limit of cargo (Panté and Kann, 2002) and the suggested dynamic nature of the central transporting module (Beck et al., 2004; Schwarz-Herion et al., 2007; Solmaz et al., 2011). "
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    ABSTRACT: The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules. It is assembled from multiple copies of about 30 nucleoporins. Due to its size and complex composition, determining the structure of the NPC is an enormous challenge, and the overall architecture of the NPC scaffold remains elusive. In this study, we have used an integrated approach based on electron tomography, single-particle electron microscopy, and crosslinking mass spectrometry to determine the structure of a major scaffold motif of the human NPC, the Nup107 subcomplex, in both isolation and integrated into the NPC. We show that 32 copies of the Nup107 subcomplex assemble into two reticulated rings, one each at the cytoplasmic and nuclear face of the NPC. This arrangement may explain how changes of the diameter are realized that would accommodate transport of huge cargoes.
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