Self-regulation of the nuclear pore complex enables clogging-free crowded transport

Abstract

Nuclear pore complexes (NPCs) are the main conduits for macromolecular transport into and out of the nucleus of eukaryotic cells. The central component of the NPC transport mechanism is an assembly of intrinsically disordered proteins (IDPs) that fills the NPC channel. The channel interior is further crowded by large numbers of simultaneously translocating cargo-carrying and free transport proteins. How the NPC can efficiently, rapidly and selectively transport varied cargoes in such crowded conditions remains ill understood. Past experimental results suggest that the NPC is surprisingly resistant to clogging and that transport may even become faster and more efficient as the concentration of transport protein increases. To understand the mechanisms behind these puzzling observations, we construct a computational model of the NPC comprising only a minimal set of commonly-accepted consensus features. This model qualitatively reproduces the previous experimental results and identifies self-regulating mechanisms that relieve crowding. We show that some of the crowding-alleviating mechanisms -- such as preventing saturation of the bulk flux -- are "robust" and rely on very general properties of crowded dynamics in confined channels, pertaining to a broad class of selective transport nanopores. By contrast, the counter-intuitive ability of the NPC to leverage crowding to achieve more efficient single molecule translocation is "fine-tuned" and relies on the particular spatial architecture of the IDP assembly in the NPC channel.

Improving the hole picture: towards a consensus on the mechanism of nuclear transport

“…We are thus faced with accounting for how three quarters or more of the CT's mass contributes to its transport behavior, and this realization has led to a recent shift in focus, onto the interplay between FG repeats and NTRs, rather than just the FG repeats alone (54). Crucially, this high concentration of NTRs and cargoes in the NPC, all specifically enriching around the FG repeats, can outcompete and so inhibit nonspecific macromolecular exchange which cannot interact with FG repeats (31,55,56).…”

Effects of Sequence Composition, Patterning and Hydrodynamics on the Conformation and Dynamics of Intrinsically Disordered Proteins

“…Emerging evidence shows that, due to their disordered nature and the importance of entropic effects, IDP structural ensembles might be less sensitive to the fine details of a specific amino acid sequence compared to the unique 3D structures of the classical folded proteins. Rather, many IDP properties can often be understood in terms of global characteristics such as the overall charge, hydrophobicity, flexibility of the polypeptide backbone and the average solvent properties [ 14 , 15 , 16 , 17 , 18 , 19 ]. Typically, the mean hydrophobicity is lower and the mean net charge is higher in IDP sequences than in folded proteins, and they are impoverished in large amino acids, preventing the folding of IDPs into unique stable structures with a hydrophobic core [ 12 , 20 ].…”