bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–02–12
two papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Self-regulation of the nuclear pore complex enables clogging-free crowded transport.
  2. Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length.
  1. Proc Natl Acad Sci U S A. 2023 Feb 14. 120(7): e2212874120
    Self-regulation of the nuclear pore complex enables clogging-free crowded transport.
    Tiantian Zheng, Anton Zilman.
      Nuclear pore complexes (NPCs) are the main conduits for macromolecular transport into and out of the nucleus of eukaryotic cells. The central component of the NPC transport mechanism is an assembly of intrinsically disordered proteins (IDPs) that fills the NPC channel. The channel interior is further crowded by large numbers of simultaneously translocating cargo-carrying and free transport proteins. How the NPC can efficiently, rapidly, and selectively transport varied cargoes in such crowded conditions remains ill understood. Past experimental results suggest that the NPC is surprisingly resistant to clogging and that transport may even become faster and more efficient as the concentration of transport protein increases. To understand the mechanisms behind these puzzling observations, we construct a computational model of the NPC comprising only a minimal set of commonly accepted consensus features. This model qualitatively reproduces the previous experimental results and identifies self-regulating mechanisms that relieve crowding. We show that some of the crowding-alleviating mechanisms-such as preventing saturation of the bulk flux-are "robust" and rely on very general properties of crowded dynamics in confined channels, pertaining to a broad class of selective transport nanopores. By contrast, the counterintuitive ability of the NPC to leverage crowding to achieve more efficient single-molecule translocation is "fine-tuned" and relies on the particular spatial architecture of the IDP assembly in the NPC channel.
    Keywords:  crowding; nuclear pore complex; nucleocytoplasmic transport; self-regulation
    DOI:  https://doi.org/10.1073/pnas.2212874120
  2. Nat Commun. 2023 Feb 10. 14(1): 747
    Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length.
    Sheung Chun Ng, Abin Biswas, Trevor Huyton, Jürgen Schünemann, Simone Reber, Dirk Görlich.
      Nup98 FG repeat domains comprise hydrophobic FG motifs linked through uncharged spacers. FG motifs capture nuclear transport receptors (NTRs) during nuclear pore complex (NPC) passage, confer inter-repeat cohesion, and condense the domains into a selective phase with NPC-typical barrier properties. We show that shortening inter-FG spacers enhances cohesion, increases phase density, and tightens such barrier - all consistent with a sieve-like phase. Phase separation tolerates mutating the Nup98-typical GLFG motifs, provided domain-hydrophobicity remains preserved. NTR-entry, however, is sensitive to (certain) deviations from canonical FG motifs, suggesting co-evolutionary adaptation. Unexpectedly, we observed that arginines promote FG-phase-entry apparently also by hydrophobic interactions/ hydrogen-bonding and not just through cation-π interactions. Although incompatible with NTR·cargo complexes, a YG phase displays remarkable transport selectivity, particularly for engineered GFPNTR-variants. GLFG to FSFG mutations make the FG phase hypercohesive, precluding NTR-entry. Extending spacers relaxes this hypercohesion. Thus, antagonism between cohesion and NTR·FG interactions is key to transport selectivity.
    DOI:  https://doi.org/10.1038/s41467-023-36331-4
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