TCB Publications - Abstract

Ramya Gamini, Wei Han, John E. Stone, and Klaus Schulten. Assembly of Nsp1 nucleoporins provides insight into nuclear pore complex gating. PLoS Computational Biology, 10:e1003488, 2014. (14 pages). (PMC: PMC3952814)

GAMI2014 Nuclear pore complexes (NPCs) are gateways for passage of material across the nuclear envelope of eukaryotic cells. Several unstructured proteins, rich in phenylaline- glycine motifs (FG-nups), form the central transport channel. Small molecules passively diffuse through, but larger molecules need transport factors, that pass apparently by means of interaction with the FG-repeats of the nups in the channel. Understanding how nups are arranged in the interior of the NPC may explain why large molecules pass only when assisted by transport factors. We employed coarse-grained molecular dynamics simulations to simulate the structures formed by various assemblies of one kind of nup, namely the 609-aa-long Nsp1. The simulations started from different initial conformations and geometrical arrangements of Nsp1s. In all cases Nsp1s collectively formed brush-like structures with bristles made of bundles of 2-27 nups, however, the bundles being cross-linked through single nups leaving one bundle and joining a nearby one. The degree of cross-linking varies with different initial nup conformations and arrangements. The structures formed are independent of FG-repeats, indicating that FGs act only as interaction sites for transport factors, but are not structural determinants of the NPC pore interior. The simulations suggest then that the NPC central channel, near the periphery where tethering of nups is dominant, features brush-like moderately cross- linked bundles, but in the central region, where tethering looses its effect, features a sieve-like structure of bundles and frequent cross-links. The cross-linking between Nsp1 bundles simulated is found to set a molecular size limit of $\textless$9 nm for passive diffusion of molecules. Larger biomolecules need to bind to transport factors to pass through nuclear pores; the transport factors must have the ability to melt the cross-linking between nups bundles creating, thereby, wide enough space for themselves and their cargoes to pass.

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