Nucleocytoplasmic transport occurs through the nuclear pore complex (NPC), which 
in yeast is a ~50 MDa complex consisting of ~30 different proteins. Small 
molecules can freely exchange through the NPC, but macromolecules larger than 
~40 kDa must be aided across by transport factors, most of which belong to a 
related family of proteins termed karyopherins (Kaps). These transport factors 
bind to the disordered phenylalanine-glycine (FG) repeat domains in a family of 
NPC proteins termed FG nups, and this specific binding allows the transport 
factors to cross the NPC. However, we still know little in terms of the 
molecular and kinetic details regarding how this binding translates to selective 
passage of transport factors across the NPC. Here we show that the specific 
interactions between Kaps and FG nups are strongly modulated by the presence of 
a cellular milieu whose proteins appear to act as very weak competitors that 
nevertheless collectively can reduce Kap/FG nup affinities by several orders of 
magnitude. Without such modulation, the avidities between Kaps and FG nups 
measured in vitro are too tight to be compatible with the rapid transport 
kinetics observed in vivo. We modeled the multivalent interactions between the 
disordered repeat binding sites in the FG nups and multiple cognate binding 
sites on Kap, showing that they should indeed be sensitive to even weakly 
binding competitors; the introduction of such competition reduces the 
availability of these binding sites, dramatically lowering the avidity of their 
specific interactions and allowing rapid nuclear transport.