I like to move it, move it

Cell 163, 734–745 (2015)

The nuclear pore complex (NPC) is an enormous macromolecular structure that mediates the passage of proteins from the nucleus to the cytoplasm and vice versa. Phenylalanine-glycine–rich nucleoporins (FG-Nups) are intrinsically disordered proteins that line the pore of the NPC, preventing larger proteins (>40 kDa) that are not bound to nuclear transport receptors (NTRs) from moving through the nuclear pore. Milles et al. used NMR spectroscopy to show that the ProXxxPheGly-rich domain of Nup153 (Nup153FG^PxFG) is highly disordered in solution, with very little secondary structure. Only minor changes in the NMR spectrum were observed when importin β was present, indicating that the binding of this NTR to Nup153FG^PxFG does not markedly alter the disordered structure of the nucleoporin. Single-molecule Förster resonance energy transfer experiments on Nup153FG^PxFG and full-length Nup153FG confirmed that the overall structure of this nucleoporin does not change substantially when it is bound to importin β. Unbiased molecular dynamics simulations of different conformations of Nup153FG^PxFG and the N-terminal portion of importin β suggested that the presence of many solvent-exposed phenylalanines in the FG repeats means that importin β can easily bind to them without either protein undergoing substantial conformational changes. The authors then used fluorescence stopped-flow experiments and Brownian dynamics simulations to show that the binding of full-length Nup153FG to importin β is extremely rapid, even when high-ionic-strength buffers are used to diminish the effects of any potential long-range electrostatic interactions between the two proteins. These experiments indicate a transient and highly dynamic binding mode that allows importin β to quickly 'creep' through the FG motifs that line the nuclear pore until it reaches the nucleus. The authors found similar results for several other Nups and NTRs, suggesting that this may be a general mechanism by which this family of intrinsically disordered proteins is able to be selective for so many structurally diverse nuclear transport receptors on such a fast timescale.