Journal
CELL
Volume 163, Issue 3, Pages 734-745Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.09.047
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Funding
- Boehringer Ingelheim Fonds (BIF)
- EMBO long-term fellowship [ALTF 4682014]
- EC via Marie Curie Action [EMBOCOFUND2012, GA-2012-600394]
- BIF short-term fellowship
- Wellcome Trust [WT/095195]
- Emmy Noether program of the DFG
- Klaus Tschira Foundation
- BIOMS program of Heidelberg University
- [SFB1129]
- MRC [MC_U105485808] Funding Source: UKRI
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The mechanisms by which intrinsically disordered proteins engage in rapid and highly selective binding is a subject of considerable interest and represents a central paradigmto nuclear porecomplex (NPC) function, where nuclear transport receptors (NTRs) move through the NPC by binding disordered phenylalanine- glycine-rich nucleoporins (FG-Nups). Combining single-molecule fluorescence, molecular simulations, and nuclear magnetic resonance, we show that a rapidly fluctuating FG-Nup populates an ensemble of conformations that are prone to bind NTRs with near diffusion-limited on rates, as shown by stopped-flow kinetic measurements. This is achieved using multiple, minimalistic, low-affinity binding motifs that are in rapid exchange when engaging with the NTR, allowing the FG-Nup to maintain an unexpectedly high plasticity in its bound state. We propose that these exceptional physical characteristics enable a rapid and specific transport mechanism in the physiological context, a notion supported by single molecule in-cell assays on intact NPCs.
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