A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies

Abstract

The permeability barrier of nuclear pore complexes (NPCs) controls bulk nucleocytoplasmic exchange. It consists of nucleoporin domains rich in phenylalanine-glycine motifs (FG domains). As a bottom-up nanoscale model for the permeability barrier, we have used planar films produced with three different end-grafted FG domains, and quantitatively analyzed the binding of two different nuclear transport receptors (NTRs), NTF2 and Importin β, together with the concomitant film thickness changes. NTR binding caused only moderate changes in film thickness; the binding isotherms showed negative cooperativity and could all be mapped onto a single master curve. This universal NTR binding behavior – a key element for the transport selectivity of the NPC – was quantitatively reproduced by a physical model that treats FG domains as regular, flexible polymers, and NTRs as spherical colloids with a homogeneous surface, ignoring the detailed arrangement of interaction sites along FG domains and on the NTR surface.DOI: http://dx.doi.org/10.7554/eLife.14119.001

Intrinsically disordered nuclear pore proteins show ideal-polymer morphologies and dynamics

“…By defining FG nups down to their specific amino acid composition, such models can relate, e.g., FG nup behaviour to their chemical composition and can explore the effects of mutations [18][19][20], with the important caveat that the results critically depend on a large number of parameters describing the various sizes, charges, and hydrophobicities of the amino acids. Complementarily, at a coarser ("mesoscale") level, FG nups have been modelled as homogeneous polymers where the electrostatic, hydrophobic, and hydrophilic interactions are incorporated into one essential interaction parameter [21,22]. Remarkably, these coarser models have reproduced key functional properties of FG nups, with and without nuclear transport receptors, as observed in experiment [21,22].…”

HEAT repeats – versatile arrays of amphiphilic helices working in crowded environments?

“…Recent studies have focused on the interaction between karyopherins and intrinsically disordered Nups that contain phenylalanine-glycine motifs (collectively referred to as FGNups) (Milles et al, 2015;Bestembayeva et al, 2015;Zahn et al, 2016). Such hydrophobic residues are believed to crosslink the flexible polypeptide chains and to form a hydrogel, a meshwork structure that prevents cellular macromolecules from passively diffusing through the nuclear pore.…”

The nuclear pore complex core scaffold and permeability barrier: variations of a common theme

“…In support of the selective phase model, Zahn et al . interpreted that an FG layer on a surface, as quantified by quartz crystal microbalance with dissipation analysis, is significantly more compact than a theoretical non-cohesive polymer brush, suggesting a ‘pore-filling cohesive meshwork’ or ‘condensed polymer brush’ resulting from FG–FG cohesion in a nano-confined NPC milieux [52]. However, future analyses should address the existence of such NPC hydrogel structures or cohesive meshworks in vivo .…”