Efficiency, Selectivity, and Robustness of Nucleocytoplasmic Transport

Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, United States
PLoS Computational Biology (Impact Factor: 4.83). 08/2007; 3(7):e125. DOI: 10.1371/journal.pcbi.0030125
Source: PubMed

ABSTRACT All materials enter or exit the cell nucleus through nuclear pore complexes (NPCs), efficient transport devices that combine high selectivity and throughput. NPC-associated proteins containing phenylalanine-glycine repeats (FG nups) have large, flexible, unstructured proteinaceous regions, and line the NPC. A central feature of NPC-mediated transport is the binding of cargo-carrying soluble transport factors to the unstructured regions of FG nups. Here, we model the dynamics of nucleocytoplasmic transport as diffusion in an effective potential resulting from the interaction of the transport factors with the flexible FG nups, using a minimal number of assumptions consistent with the most well-established structural and functional properties of NPC transport. We discuss how specific binding of transport factors to the FG nups facilitates transport, and how this binding and competition between transport factors and other macromolecules for binding sites and space inside the NPC accounts for the high selectivity of transport. We also account for why transport is relatively insensitive to changes in the number and distribution of FG nups in the NPC, providing an explanation for recent experiments where up to half the total mass of the FG nups has been deleted without abolishing transport. Our results suggest strategies for the creation of artificial nanomolecular sorting devices.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intrinsically disordered Phe-Gly nucleoporins (FG Nups) within nuclear pore complexes exert multivalent interactions with transport receptors (Karyopherins (Kaps)) that orchestrate nucleocytoplasmic transport. Current FG-centric views reason that selective Kap translocation is promoted by alterations in the barrier-like FG Nup conformations. However, the strong binding of Kaps with the FG Nups due to avidity contradicts rapid Kap translocation in vivo. Here, using surface plasmon resonance, we innovate a means to correlate in situ mechanistic (molecular occupancy and conformational changes) with equilibrium (binding affinity) and kinetic (multivalent binding kinetics) aspects of Karyopherinβ1 (Kapβ1) binding to four different FG Nups. A general feature of the FxFG domains of Nup214, Nup62, and Nup153 is their capacity to extend and accommodate large numbers of Kapβ1 molecules at physiological Kapβ1 concentrations. A notable exception is the GLFG domain of Nup98, which forms a partially penetrable cohesive layer. Interestingly, we find that a slowly exchanging Kapβ1 phase forms an integral constituent within the FG Nups that coexists with a fast phase, which dominates transport kinetics due to limited binding with the pre-occupied FG Nups at physiological Kapβ1 concentrations. Altogether, our data reveal an emergent Kap-centric barrier mechanism that may underlie mechanistic and kinetic control in the nuclear pore complex.
    Biophysical Journal 04/2014; 106(8):1751-62. DOI:10.1016/j.bpj.2014.02.021 · 3.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The transport of cargo across the nuclear membrane is highly selective and accomplished by a poorly understood mechanism involving hundreds of nucleoporins lining the inside of the nuclear pore complex (NPC). Currently, there is no clear picture of the overall structure formed by this collection of proteins within the pore, primarily due to their disordered nature. We perform coarse-grained simulations of both individual nucleoporins and grafted rings of nups mimicking the in vivo geometry of the NPC and supplement this with polymer brush modeling. Our results indicate that different regions or blocks of an individual NPC protein can have distinctly different forms of disorder and that this property appears to be a conserved functional feature. Furthermore, this block structure at the individual protein level is critical to the formation of a unique higher-order polymer brush architecture that can exist in distinct morphologies depending on the effective interaction energy between the phenylalanine glycine (FG) domains of different nups. Because the interactions between FG domains may be modulated by certain forms of transport factors, our results indicate that transitions between brush morphologies could play an important role in regulating transport across the NPC, suggesting novel forms of gated transport across membrane pores with wide biomimetic applicability.
    Biophysical Journal 05/2014; 106(9):1997-2007. DOI:10.1016/j.bpj.2014.03.021 · 3.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: By using an exclusion model, in this work we address how the non-uniform occupancy of a nanochannel, for a limited set of conditions, is related to the transport of specific molecules through it. The results show that the shape of a channel greatly influences its transporting behavior and therefore, it can be used as a tunable parameter to achieve a desired set of transporting conditions. In particular, we have found that for applications which require a highly selective channel that is able to handle large input fluxes of specific particles in both directions, a double-funnel architecture is the best suited. As the obtained results mainly arise from the competition of particles for limited space, we expect them to be applicable to a great variety of transporting phenomena where the channel has a limited number of interacting sites with the transported particles.
    Journal of Statistical Physics 01/2014; 158(2):494-512. DOI:10.1007/s10955-014-1132-6 · 1.28 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014