B1

Nup358
Nupl53

^rgl RanGTP

Fig. 5. Current models of translocation through the nuclear pore complex. (A) The virtual gating model of Rout et al. (12); (B1) the model of Stewart et al. (111); (B2) the oily spaghetti model of Macara (8); (B3) the affinity gradient model of Ben-Efraim and Gerace (112); and (C) the selective phase model of Ribbeck and Gorlich (67). (A) From ref. 12, © 2003, with permission from Elsevier; (B1) from ref. 111; (B2) from ref. 8 with permission; (B3) from ref. 112, with permission from The Rockefeller University Press; (C) from ref. 67 (http://www.nature.com).

In the "virtual gating model" (Fig. 5A) it is assumed (12,52) that the NPC contains a large patent channel of approx 50 nm diameter. The channel entrance but not the channel wall is thought to be decorated with a large number of small flexible protein filaments carrying an abundance of binding sites, i.e. FG motifs. The channel would constitute a large energy barrier for the translocation of inert molecules, even if they are much smaller than the channel diameter. In addition, the small, flexible FG repeat containing filaments would push away inert molecules by thermal motion. In contrast, transport receptors or transport complexes which would be concentrated at the channel entrance by binding to FG repeats. This would reduce the energy barrier for entering the channel and thus enhance translocation. Experimentally, little is known about the distribution of FG motifs along the axis of the NPC. Data we have obtained by immunogold electron microscopy (118) and by single-molecule fluorescence microscopy (119) suggest that binding sites of transport receptors occur all along the NPC axis. Deletion experiments have shown (56) that in yeast the FG motifs of asymmetric nucleoporins can be completely removed without compromising growth properties.

Stewart et al. (111,120) also assume that the NPC contains a large channel. However, in their model (Fig. 5B1) binding sites (i.e. FG repeats) are distributed along the complete transport pathway, that is, from the tips of the cytoplasmic filaments throughout the channel down to the nuclear basket. An import complex, for instance, would bind to FG repeats of the cytoplasmic filaments, jump from one FG repeat to the next, and thus pass through the central channel. In arriving in the nuclear basket, it would encounter RanGTP and dissociate. Similarly, in the "oily-spaghetti model" (8) (Fig. 5B2) the wall of the central channel is decorated with a loose and highly flexible meshwork of FG repeats. The filaments extend into the channel lumen but leave free a diffusion tube approx 10 nm in diameter. Thus, the passage of inert molecules would be restricted to the diffusion tube but transport receptors and transport complexes would be able to use the complete cross section of the channel because of their affinity for FG repeats.

Ben-Efraim and Gerace (112) found that the nucleoporins vNup358, vNup62, and vNup153, which localize to cytoplasmic filament, central scaffold, and nuclear basket, respectively, display increasing affinities for karyopherin P1. They suggested that the gradient of increasing affinity found in vitro using purified proteins also exists in vivo. Thus (Fig. 5B3), import complexes would be handed over from a nucleoporin with a lower affinity to an neighboring nucleoporin with higher affinity until they arrive in the nuclear basket where they are dissociated by interaction with RanGTP. Recent experiments (121) in which the FG domains of asymmetric cytoplasmic and nuclear yeast nucleoporins were either deleted or exchanged did not revealed, however, any effect of these modifications on transport.

In the selective-phase model (67) the NPC contains a large channel which is occluded by a gel. That gel is thought to be formed by FG domains such that the hydrophobic FG motifs interact with each other to yield "knots" while the hydrophilic linker sequences provide the connections between knots. To permeate through the NPC inert molecules would have to slip through the rather small meshes of the gel. In contrast, transport receptors and transport complexes would be able to interact with FG motifs and thus to temporarily open the knots . In accordance with the model small

Fig. 6. Reduction-of-dimensionality model of translocation through the nuclear pore complex. (A) The nuclear pore complex (NPC) is assumed to contain a large channel. The channel wall is lined with phenylalanine glycine (FG) motifs (i.e., binding sites for nuclear transport receptors). FG repeats form a surface that extends onto filaments. (B) The channel wall is decorated with a loose network of unfolded hydrophilic peptide chains, here referred to selectivity filter. The selectivity filter is very gentle and flexible. (C) Inert molecules, which do not bind to FG motifs, permeate the pore by diffusion in the aqueous phase. The selectivity filter restricts the passage to an inner tube with a diameter of 5 to 10 nm. (D) Transport complexes, which consist of a nuclear signal containing cargo and a nuclear transport receptor, first bind to FG motifs on filaments and then search the FG surface by a 2D random walk for the site with highest affinity. From ref. 116.

Fig. 6. Reduction-of-dimensionality model of translocation through the nuclear pore complex. (A) The nuclear pore complex (NPC) is assumed to contain a large channel. The channel wall is lined with phenylalanine glycine (FG) motifs (i.e., binding sites for nuclear transport receptors). FG repeats form a surface that extends onto filaments. (B) The channel wall is decorated with a loose network of unfolded hydrophilic peptide chains, here referred to selectivity filter. The selectivity filter is very gentle and flexible. (C) Inert molecules, which do not bind to FG motifs, permeate the pore by diffusion in the aqueous phase. The selectivity filter restricts the passage to an inner tube with a diameter of 5 to 10 nm. (D) Transport complexes, which consist of a nuclear signal containing cargo and a nuclear transport receptor, first bind to FG motifs on filaments and then search the FG surface by a 2D random walk for the site with highest affinity. From ref. 116.

alcohols that perturb hydrophobic interactions were found to cause a large increase in the passive permeability of the NPC (122).

Results obtained by optical transport measurements (16) and single-molecule fluorescence microscopy (119) prompted us suggested a translocation model (116) in which the enhancement of transport by binding is accounted for by the fundamental differences (123) existing between diffusion in two and three dimensions. In the model (Fig. 6) it is assumed that the wall of the channel traversing the NPC is covered with a dense array of FG motifs forming one, coherent hydrophobic surface. The FG surface is thought to continue on cytoplasmic filaments and on parts of the nuclear filaments (Fig. 6A). In addition to the FG surface, the model includes a loose network of flexible, hydrophilic, possibly glycosylated peptide chains decorating the central part of the channel wall (Fig. 6B). The loose network extends into the pore lumen but leaves free a central tube with a approx 10-nm diameter.

Inert molecules (Fig. 6C) are thought to permeate the NPC by diffusing through the inner water-filled central tube. In contrast, transport receptors and transport complexes (Fig. 6D) would bind to the FG surface on filaments and then rapidly search the FG surface for the channel exit by a two-dimensional random walk . At the exit the transport complexes would encounter either RanGTP (import) or RanBP and RanGAP and thus be dissociated. Further properties, implications, and predictions of the model are discussed elsewhere (116).

5. Concluding Remarks

The elucidation of nucleocytoplasmic transport has made tremendous progress. Excitingly, the full power of the eukaryotic building plan, segregating genetic material from protein synthesis, is in gradual disclosure. Better understanding of nucleo-cytoplasmic transport will have important implications for both medicine and biotechnology. Already, the role of nucleocytoplasmic transport in the biogenesis of pathological conditions and the possibilities for new therapeutic strategies are intensively studied. Apart from this, the NPC provides an intriguing paradigm for a molecular machine able to sort native protein molecules at high speed.

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