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: 4.62). 08/2007; 3(7):e125. DOI: 10.1371/journal.pcbi.0030125
Source: PubMed


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.


Available from: Michael P Rout
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    • "Therefore, while nonspecific molecules could also bind weakly to FG Nups and in principle pass through the channel, the exchange of transport factors across the NPC, either cargo-laden or free, would sweep these nonspecific molecules out of the central channel, the more strongly binding transport factors effectively out-competing the weaker binding nonspecific molecules. This competition effect has been both predicted theoretically (Zilman et al. 2007, 2010) and measured experimentally in an artificial yeast NPC (Jovanovic-Talisman et al. 2009). In effect, the transport factors may be acting as bouncers at the NPC gate, excluding nonspecific macromolecules and so appearing to be important components of the selectivity barrier. "
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    ABSTRACT: Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell's genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or "Nups"), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC's role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins.
    Genetics 03/2012; 190(3):855-83. DOI:10.1534/genetics.111.127803 · 5.96 Impact Factor
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    • "Several models have been proposed to explain selective translocation through the NPC, including a high density of low affinity binding sites, partitioning based on hydrophobicity or gel-like states within the channel, reduction of dimensionality by KAP binding to the FG-NUPs and more formal gating systems [18][19][20][21][22]. Recent work suggests that selectivity can arise from a balance between efficiency and speed of transport for each KAP-β•cargo complex [23]. While no consensus mechanism has emerged, FG-NUPs clearly have a major role as these disordered proteins selectively bind KAP-β complexes [24], concentrate them at the NPC and restrict passive diffusion [18]. "
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    ABSTRACT: Macromolecular transport across the nuclear envelope (NE) is achieved through nuclear pore complexes (NPCs) and requires karyopherin-βs (KAP-βs), a family of soluble receptors, for recognition of embedded transport signals within cargo. We recently demonstrated, through proteomic analysis of trypanosomes, that NPC architecture is likely highly conserved across the Eukaryota, which in turn suggests conservation of the transport mechanisms. To determine if KAP-β diversity was similarly established early in eukaryotic evolution or if it was subsequently layered onto a conserved NPC, we chose to identify KAP-β sequences in a diverse range of eukaryotes and to investigate their evolutionary history. Thirty six predicted proteomes were scanned for candidate KAP-β family members. These resulting sequences were resolved into fifteen KAP-β subfamilies which, due to broad supergroup representation, were most likely represented in the last eukaryotic common ancestor (LECA). Candidate members of each KAP-β subfamily were found in all eukaryotic supergroups, except XPO6, which is absent from Archaeplastida. Phylogenetic reconstruction revealed the likely evolutionary relationships between these different subfamilies. Many species contain more than one representative of each KAP-β subfamily; many duplications are apparently taxon-specific but others result from duplications occurring earlier in eukaryotic history. At least fifteen KAP-β subfamilies were established early in eukaryote evolution and likely before the LECA. In addition we identified expansions at multiple stages within eukaryote evolution, including a multicellular plant-specific KAP-β, together with frequent secondary losses. Taken with evidence for early establishment of NPC architecture, these data demonstrate that multiple pathways for nucleocytoplasmic transport were established prior to the radiation of modern eukaryotes but that selective pressure continues to sculpt the KAP-β family.
    PLoS ONE 04/2011; 6(4):e19308. DOI:10.1371/journal.pone.0019308 · 3.23 Impact Factor
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    • "Instead, they may guide the directionality of transport-factor/cargo complexes by providing a high-affinity binding platform at the far end of a transport factor's route through the NPC. A transport factor would be drawn to this site and prevented by it from returning through the NPC until Ran terminates the transport reaction , in this way increasing the efficiency of transport (Rout et al. 2003; Strawn et al. 2004; Zilman et al. 2007). "
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    ABSTRACT: Internal membrane bound structures sequester all genetic material in eukaryotic cells. The most prominent of these structures is the nucleus, which is bounded by a double membrane termed the nuclear envelope (NE). Though this NE separates the nucleoplasm and genetic material within the nucleus from the surrounding cytoplasm, it is studded throughout with portals called nuclear pore complexes (NPCs). The NPC is a highly selective, bidirectional transporter for a tremendous range of protein and ribonucleoprotein cargoes. All the while the NPC must prevent the passage of nonspecific macromolecules, yet allow the free diffusion of water, sugars, and ions. These many types of nuclear transport are regulated at multiple stages, and the NPC carries binding sites for many of the proteins that modulate and modify the cargoes as they pass across the NE. Assembly, maintenance, and repair of the NPC must somehow occur while maintaining the integrity of the NE. Finally, the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation. All these requirements demonstrate the complex design of the NPC and the integral role it plays in key cellular processes.
    Cold Spring Harbor perspectives in biology 10/2010; 2(10):a000562. DOI:10.1101/cshperspect.a000562 · 8.68 Impact Factor
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