Physical theory of nucleo-cytoplasmic transport
; transport factors with the meshwork of fluctuating filaments Short Abstract — Proper functioning of all eukaryotic cells inside the pore. depends critically on the transport of macromolecules between The first question we address is how binding to the pore the cell nucleus and the cytoplasm, which proceeds through the can enhance the transport efficiency. The theory shows that the nuclear pore complexes (NPC). Several characteristics of the macromolecules that do not interact with the pore have a the NPC transport make it distinct from other common forms very low probability of traversing it. By contrast, binding of of biological transport. In addition to being central biological the transport proteins to the pore increases the time they question, the transport through the NPC poses challenging spend inside the pore, but also increases the probability to physical problems. We develop a physical theory of transport traverse it . through the NPC that explains its functional properties in
Limitations of space inside the pore lead to the terms of its structure. In particular, we propose a novel
mechanism of selectivity enhancement that does not require competition between translocating cargoes, and at too high input of metabolic energy. The theory can be extended to other binding affinities, the pore becomes jammed. This leads to a signaling mechanisms, and suggests strategies for creation of preferential binding affinity that optimizes the transport, and artificial nano-molecular sorting devices. provides the mechanism for the selectivity .
However, the predicted and measured optimal binding I. BACKGROUND affinity is relatively low- of the order of 10-20 kT. The NPC,
however, has to filter out non-specifically binding
Proper functioning of all eukaryotic cells depends macromolecules whose binding affinity sometimes lies in the critically on the transport of macromolecules between the cell range of several kT from the optimal one. We have proposed a nucleus and the cytoplasm, which proceeds through the the novel selectivity mechanism, and shown that in the case of nuclear pore complexes (NPC). This transport is mediated direct competition between the cognate transport proteins, by transport proteins that bind their cargo in the nucleus and non-specific cargoes, the selectivity increases far beyond (or the cytoplasm), and transport it through the NPC [1,2]. In the differences in the equilibrium binding affinities, and the milliseconds time , the NPCs are able to selectively non-specific cargoes are essentially filtered out . transmit - over the background of vast amount of Finally, we have shown how the flexibility of the filaments non-specifically interacting macromolecules - only the makes the transport relatively insensitive to their total cargoes that are bound to the transport proteins. number. Due to the thermal fluctuations of flexible filaments,
Remarkably, this fast and highly selective filtering the transport proteins can diffuse while still attached to a does not require an active input of metabolic energy, and filament, and transfer to the next one. This makes the occurs purely by diffusion. Moreover, unlike common ‘lock transport insensitive to the total number of filaments as long and key’ transport gating mechanisms, the NPC is always as the regions of their fluctuations overlap . in the ‘open’ state, known as ‘virtual gating’ . The mechanism of transport that we studied have various
Internal space of the pore and large parts of its nulclear other biological applications. The proposed selectivity and cytoplasmic surfaces, are filled by unfolded, flexible mechanism apply to other modes of biological signaling, e.g. poly-peptide chains that create the permeability barrier. A transport through narrow channels, and cascades of crucial component of the selective NPC transport is the enzymatic reactions, and suggest strategies for creation of transient binding of the transport proteins to this unfolded artificial molecular sorting devices.
filaments. Strikingly, the NPCs have been shown to Finally, understanding the mechanism of transport function even when a large fraction of the material through the NPC in molecular detail is important for comprising the pore is deleted . designing efficient strategies of combating viral infections by
We have developed a physical theory of transport preventing their entry to the cell nucleus. through the nuclear pore complex, which rigorously models the diffusion of the transport proteins through the REFERENCES meshwork of fluctuating filaments, controlled by the  E. J. Tran, and S.R. Wente. 2006. Dynamic nuclear pore complexes: transient binding to the filaments . life on the edge. Cell. 125:1041-53.  M. P. Rout, J.D. Aitchison, M.O. Magnasco, and B.T. Chait. 2003. II. RESULTS OF THE MODEL Virtual gating and nuclear transport: the hole picture. Trends Cell Biol. 13:622-8  A. Zilman, S. Di Talia, B. Chait, M. Magnasco, M. Rout, Efficiency, Using analytical theory, and computer simulations, we Selectivity and Robustness of nucleo-cytoplasmic Transport, have modeled the transport through the NPC as diffusion in Submitted an effective potential, determined by the interactions of the
; 1 Affiliation: CNLS and T-10, Los Alamos National Laboratory
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