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Effect of charge, hydrophobicity, and sequence of nucleoporins on the translocation of model particles through the nuclear pore complex.

ABSTRACT: The molecular structure of the yeast nuclear pore complex (NPC) and the translocation of model particles have been studied with a molecular theory that accounts for the geometry of the pore and the sequence and anchoring position of the unfolded domains of the nucleoporin proteins (the FG-Nups), which control selective transport through the pore. The theory explicitly models the electrostatic, hydrophobic, steric, conformational, and acid-base properties of the FG-Nups. The electrostatic potential within the pore, which arises from the specific charge distribution of the FG-Nups, is predicted to be negative close to pore walls and positive along the pore axis. The positive electrostatic potential facilitates the translocation of negatively charged particles, and the free energy barrier for translocation decreases for increasing particle hydrophobicity. These results agree with the experimental observation that transport receptors that form complexes with hydrophilic/neutral or positively charged proteins to transport them through the NPC are both hydrophobic and strongly negatively charged. The molecular theory shows that the effects of electrostatic and hydrophobic interactions on the translocating potential are cooperative and nonequivalent due to the interaction-dependent reorganization of the FG-Nups in the presence of the translocating particle. The combination of electrostatic and hydrophobic interactions can give rise to complex translocation potentials displaying a combination of wells and barriers, in contrast to the simple barrier potential observed for a hydrophilic/neutral translocating particle. This work demonstrates the importance of explicitly considering the amino acid sequence and hydrophobic, electrostatic, and steric interactions in understanding the translocation through the NPC.

SUBMITTER: Tagliazucchi M

PROVIDER: S-EPMC3587244 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Effect of charge, hydrophobicity, and sequence of nucleoporins on the translocation of model particles through the nuclear pore complex.

Tagliazucchi Mario M Peleg Orit O Kröger Martin M Rabin Yitzhak Y Szleifer Igal I

Proceedings of the National Academy of Sciences of the United States of America 20130212 9

The molecular structure of the yeast nuclear pore complex (NPC) and the translocation of model particles have been studied with a molecular theory that accounts for the geometry of the pore and the sequence and anchoring position of the unfolded domains of the nucleoporin proteins (the FG-Nups), which control selective transport through the pore. The theory explicitly models the electrostatic, hydrophobic, steric, conformational, and acid-base properties of the FG-Nups. The electrostatic potenti ...[more]

PMID: 23404701

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Project description:Nuclear pore complexes (NPCs) form gateways for material transfer across the nuclear envelope of eukaryotic cells. Disordered proteins, rich in phenylalanine-glycine repeat motifs (FG-nups), form the central transport channel. Understanding how nups are arranged in the interior of the NPC may explain how NPC functions as a selectivity filter for transport of large molecules and a sieve-like filter for diffusion of small molecules (<9 nm or 40 kDa). We employed molecular dynamics to model the structures formed by various assemblies of one kind of nup, namely the 609-aa-long FG domain of Nsp1 (Nsp1-FG). The simulations started from different initial conformations and geometrical arrangements of Nsp1-FGs. In all cases Nsp1-FGs 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. Structural analysis reveals that FG-repeats of the nups not only involve formation of bundle structures, but are abundantly present in cross-linking regions where the epitopes of FG-repeats are highly accessible. Large molecules that are assisted by transport factors (TFs) are selectively transported through NPC apparently by binding to FG-nups through populated FG-binding pockets on the TF surface. Therefore, our finding suggests that TFs bind concertedly to multiple FGs in cross-linking regions and break-up the bundles to create wide pores for themselves and their cargoes to pass. In addition, the cross-linking between Nsp1-FG bundles, arising from simulations, is found to set a molecular size limit of <9 nm (40 kDa) for passive diffusion of molecules. Our simulations suggest 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 loses its effect, features a sieve-like structure of bundles and frequent cross-links.

Dataset Information

Effect of charge, hydrophobicity, and sequence of nucleoporins on the translocation of model particles through the nuclear pore complex.

Publications

Effect of charge, hydrophobicity, and sequence of nucleoporins on the translocation of model particles through the nuclear pore complex.

Similar Datasets

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