Conformational Behavior of the Confined Fg-Repeat Domains in the Nuclear Pore

Abstract

The nuclear pore complex, NPC, is responsible for selectively conducting transport to/from the nucleus in eukaryotes. While we are entering the sixth decade of the NPC-related research and discovery, the mechanism of selectivity barrier across the pore remains elusive. This is mainly due to the fact that the exact function and mechanics of the main players of the transport process, i.e. the FG-repeats, has proved difficult to capture during transport. FG-repeat domains are natively unfolded and constitute about one third of the NPC mass. They are believed to coat the most inner layer of the pore and directly interact with cargos, thus founding the selectivity barrier. The FG-repeats are confined to the central channel, so the compact architecture of the channel makes the investigation even more challenging. Here we have established a 3D coarse-grained model of the yeast channel with all 11 known FG Nucleoporins (Nups). We extract the exact sequence of the FG Nups disordered domains and implement their length, hydrophobicity, charge, and the native grafting density in the model. Our results show that the FG-motifs are mainly concentrated toward the central part of the channel, while charged residues are predominantly near the wall. Depending on the pore diameter, FG-repeats can either make a channel-filling hydrogel or a thick lubricating layer, consistent with two different models proposed in the field. We also investigated the effect of the channel shape ranging from a perfect cylinder to an hourglass geometry and observed that the bottleneck of the hourglass shape can affect the conformational behavior of the FG-repeats, depending on its aspect ratio.