Abstract
Conformational behavior of intrinsically disordered proteins, such as Phe-Gly repeat domains, alters drastically when they are confined in, and tethered to, nan channels. This has challenged our understanding of how they serve to selectively facilitate translocation of nuclear transport receptor (NTR)-bearing macromolecules. Heterogeneous FG-repeats, tethered to the NPC interior, nonuniformly fill the channel in a diameter-dependent manner and adopt a rapid Brownian motion, thereby forming a porous and highly dynamic polymeric meshwork that percolates in radial and axial directions and features two distinguishable zones: a dense hydrophobic rod-like zone located in the center, and a peripheral low-density shell-like zone. The FG-meshwork is locally disrupted upon interacting with NTR-bearing macromolecules, but immediately reconstructs itself between 0.44 μs and 7.0 μs, depending on cargo size and shape. This confers a perpetually-sealed state to the NPC, and is solely due to rapid Brownian motion of FG-repeats, not FG-repeat hydrophobic bonds. Elongated-shaped macromolecules, both in the presence and absence of NTRs, penetrate more readily into the FG-meshwork compared to their globular counterparts of identical volume and surface chemistry, highlighting the importance of the shape effects in nucleocytoplasmic transport. These results can help our understanding of geometrical effects in, and the design of, intelligent and responsive biopolymer-based materials in nanofiltration and artificial nanopores.
Highlights
Channel[10] that accommodates a tremendous rate of transport of about 1000 translocation events per second per NPC, amounting to over 100 MDa/s/NPC11
The permission to pass through the permeability barrier is granted to a macromolecule only if it is bound to a nuclear transport receptor (NTR), which carries hydrophobic binding spots on the surface and possesses a net negative charge[12]
The conformational studies on FG-repeats have mainly focused on the single-type FG-Nup in an unconfined geometry and typically non-tethered state, where the results are extrapolated to the heterogeneous mixture of all FG-Nups, end-tethered to the nanometer-sized confined geometry of the NPC channel[10]
Summary
Channel[10] that accommodates a tremendous rate of transport of about 1000 translocation events per second per NPC, amounting to over 100 MDa/s/NPC11. Despite more than two decades of dedicated research, the mechanistic understanding of such a robust permeability barrier is still under debate. This is mainly due to the lack of comprehensive understanding of how FG-repeats precisely behave, and which conformations they adopt within the NPC channel in vivo. The concentrated, heterogeneous mixture of delicate FG-repeats, featuring a large number of hydrophobic and charged residues, densely tethered to and confined in the nanometer-sized concave surface of the NPC channel, have concertedly made it impractical to inspect their precise conformational behavior in vivo, but even in vitro as well. As a compromise between spatiotemporal resolution and computational feasibility, coarse-grained modeling approaches have emerged recently, where the structural features are elaborated depending on the level of coarse-graining[20,21]
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