Cooperative Interactions between Different Classes of Disordered Proteins Play a Functional Role in the Nuclear Pore Complex of Baker’s Yeast

Abstract

Nucleocytoplasmic transport is highly selective, efficient, and is regulated by a poorly understood mechanism involving hundreds of disordered FG nucleoporin proteins (FG nups) lining the inside wall of the nuclear pore complex (NPC). Previous research has concluded that FG nups in Baker’s yeast (S. cerevisiae) are present in a bimodal distribution, with the “Forest Model” classifying FG nups as either di-block polymer like “trees” or single-block polymer like “shrubs”. Using a combination of coarse-grained modeling and polymer brush modeling, the function of the di-block FG nups has previously been hypothesized in the Di-block Copolymer Brush Gate (DCBG) model to form a higher-order polymer brush architecture which can open and close to regulate transport across the NPC. In this manuscript we work to extend the original DCBG model by first performing coarse grained simulations of the single-block FG nups which confirm that they have a single block polymer structure rather than the di-block structure of tree nups. Our molecular simulations also demonstrate that these single-block FG nups are likely cohesive, compact, collapsed coil polymers, implying that these FG nups are generally localized to their grafting location within the NPC. We find that adding a layer of single-block FG nups to the DCBG model increases the range of cargo sizes which are able to translocate the pore through a cooperative effect involving single-block and di-block FG nups. This effect can explain the puzzling connection between single-block FG nup deletion mutants in S. cerevisiae and the resulting failure of certain large cargo transport through the NPC. Facilitation of large cargo transport via single-block and di-block FG nup cooperativity in the nuclear pore could provide a model mechanism for designing future biomimetic pores of greater applicability.

Interactions between a fluctuating polymer barrier and transport factors together with enzyme action are sufficient for selective and rapid transport through the nuclear pore complex

“…Such free energy barriers for the NPC have indeed been calculated at different levels of approximation for the FG nup structure [24,25] and it would be interesting to extend our transport calculations to free energy barriers calculated for the full pore. It has also been reported [67] that there could be co-operativity between different types of FG nups in regulating transport and this would be another aspect to include.…”

The Role of Cohesiveness in the Permeability of the Spatial Assemblies of FG Nucleoporins

“…1 c), we have performed coarse-grained Langevin dynamics simulations (46,51). These simulations also enable us to investigate the effects of sequence heterogeneity and molecular patterning of inter-FG nup (68,69) as well as FG nup-transport protein interactions. The simulations were implemented using the molecular dynamics simulations package LAMMPS (70).…”

Enhanced Nucleocytoplasmic Transport due to Competition for Elastic Binding Sites

“…To our knowledge, both our proposed physical transport mechanism and our mathematical approach are novel. Most previous modeling work on the NPC has focused on atomistic (2,(43)(44)(45) and coarse-grained simulations (8,12,33,(46)(47)(48)(49)(50). This has illuminated many of the finer points of nuclear transport, but the detailed nature of this work makes it difficult to draw general conclusions about the driving force behind cargo translocation.…”