Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies

  1. Luke K Davis  Is a corresponding author
  2. Ian J Ford
  3. Bart W Hoogenboom  Is a corresponding author
  1. University College London, United Kingdom

Abstract

The rapid (< 1 ms) transport of biological material to and from the cell nucleus is regulated by the nuclear pore complex (NPC). At the core of the NPC is a permeability barrier consisting of intrinsically disordered Phe-Gly (FG) nucleoporins (FG Nups). Various types of nuclear transport receptors (NTRs) facilitate transport by partitioning in the FG Nup assembly, overcoming the barrier by their affinity to the FG Nups, and comprise a significant fraction of proteins in the NPC barrier. In previous work Zahn et al. (2016), we revealed a universal physical behaviour in the experimentally observed binding of two well-characterized NTRs, NTF2 and the larger Importin-β, to different planar assemblies of FG Nups, with the binding behaviour defined by negative cooperativity. This was further validated by a minimal physical model that treated the FG Nups as flexible homopolymers and the NTRs as uniformly cohesive spheres. Here, we build upon our original study by first parametrizing our model to experimental data, and next predicting the effects of crowding by different types of NTRs. We show how varying the amounts of one type of NTR modulates how the other NTR penetrates the FG Nup assembly. Notably, at similar and physiologically relevant NTR concentrations, our model predicts demixed phases of NTF2 and Imp-β within the FG Nup assembly. The functional implication of NTR phase separation is that NPCs may sustain separate transport pathways that are determined by inter-NTR competition.

Data availability

The source code used to generate all the simulation data in this manuscript is available on the Github repository: https://github.com/patherlkd/DFT-polymer-colloid.Figure 1 - Source Code 1 - Simulation parameters for the classical density functional theory code.Figure 3 - Source Code 1 - Simulation parameters for the classical density functional theory code.

The following data sets were generated

Article and author information

Author details

  1. Luke K Davis

    Department of Physics and Astronomy, University College London, London, United Kingdom
    For correspondence
    luke.davis@uni.lu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4487-4159
  2. Ian J Ford

    Department of Physics and Astronomy, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Bart W Hoogenboom

    London Centre for Nanotechnology, University College London, London, United Kingdom
    For correspondence
    b.hoogenboom@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8882-4324

Funding

Engineering and Physical Sciences Research Council (EP/L504889/1)

  • Luke K Davis

Engineering and Physical Sciences Research Council (EP/L504889/1)

  • Bart W Hoogenboom

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Davis et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,246
    views
  • 238
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Luke K Davis
  2. Ian J Ford
  3. Bart W Hoogenboom
(2022)
Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies
eLife 11:e72627.
https://doi.org/10.7554/eLife.72627

Share this article

https://doi.org/10.7554/eLife.72627

Further reading

    1. Physics of Living Systems
    Tommaso Amico, Samuel Toluwanimi Dada ... Amos Maritan
    Research Article

    Many proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the critical concentration, which is the concentration at which phase separation occurs. To understand this phenomenon, which is not readily compatible with classical nucleation theory, we investigated the properties of the droplet size distributions as a function of protein concentration. We found that these distributions can be described by a scale-invariant log-normal function with an average that increases progressively as the concentration approaches the critical concentration from below. The results of this scaling analysis suggest the existence of a universal behaviour independent of the sequences and structures of the proteins undergoing phase separation. While we refrain from proposing a theoretical model here, we suggest that any model of protein phase separation should predict the scaling exponents that we reported here from the fitting of experimental measurements of droplet size distributions. Furthermore, based on these observations, we show that it is possible to use the scale invariance to estimate the critical concentration for protein phase separation.

    1. Computational and Systems Biology
    2. Physics of Living Systems
    Ju Kang, Shijie Zhang ... Xin Wang
    Research Article

    Explaining biodiversity is a fundamental issue in ecology. A long-standing puzzle lies in the paradox of the plankton: many species of plankton feeding on a limited variety of resources coexist, apparently flouting the competitive exclusion principle (CEP), which holds that the number of predator (consumer) species cannot exceed that of the resources at a steady state. Here, we present a mechanistic model and demonstrate that intraspecific interference among the consumers enables a plethora of consumer species to coexist at constant population densities with only one or a handful of resource species. This facilitated biodiversity is resistant to stochasticity, either with the stochastic simulation algorithm or individual-based modeling. Our model naturally explains the classical experiments that invalidate the CEP, quantitatively illustrates the universal S-shaped pattern of the rank-abundance curves across a wide range of ecological communities, and can be broadly used to resolve the mystery of biodiversity in many natural ecosystems.