How to operate a nuclear pore complex by Kap-centric control

Nuclear pore complexes (NPCs) mediate molecular transport between the nucleus and cytoplasm in eukaryotic cells. Tethered within each NPC lie numerous intrinsically disordered proteins known as FG nucleoporins (FG Nups) that are central to this process. Over two decades of investigation has converged on a view that a barrier mechanism consisting of FG Nups rejects non-specific macromolecules while promoting the speed and selectivity of karyopherin (Kaps) receptors (and their cargoes). Yet, the number of NPCs in the cell is exceedingly small compared to the number of Kaps, so that in fact there is a high likelihood the pores are always populated by Kaps. Here, we contemplate a view where Kaps actively participate in regulating the selectivity and speed of transport through NPCs. This so-called Kap-centric control of the NPC accounts for Kaps as essential barrier reinforcements that play a prerequisite role in facilitating fast transport kinetics. Importantly, Kap-centric control reconciles both mechanistic and kinetic requirements of the NPC, and in so doing potentially resolves incoherent aspects of FG-centric models. On this basis, we surmise that Kaps prime the NPC for nucleocytoplasmic transport by fine-tuning the NPC microenvironment according to the functional needs of the cell.