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Cell. 2015 Oct 22;163(3):734-45. doi: 10.1016/j.cell.2015.09.047. Epub 2015 Oct 8.

Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors.

Author information

1
Structural and Computational Biology Unit, Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; University Grenoble Alpes, IBS, F-38044 Grenoble, France; CNRS, IBS, F-38044 Grenoble, France; CEA, IBS, F-38044 Grenoble, France.
2
Molecular Biomechanics group, HITS gGmbH, Schloß-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany; IWR - Interdisciplinary Center for Scientific Computing, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany.
3
Structural and Computational Biology Unit, Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
4
University Grenoble Alpes, IBS, F-38044 Grenoble, France; CNRS, IBS, F-38044 Grenoble, France; CEA, IBS, F-38044 Grenoble, France.
5
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
6
University Grenoble Alpes, IBS, F-38044 Grenoble, France; CNRS, IBS, F-38044 Grenoble, France; CEA, IBS, F-38044 Grenoble, France. Electronic address: martin.blackledge@ibs.fr.
7
Molecular Biomechanics group, HITS gGmbH, Schloß-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany; IWR - Interdisciplinary Center for Scientific Computing, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany. Electronic address: frauke.graeter@h-its.org.
8
Structural and Computational Biology Unit, Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: lemke@embl.de.

Abstract

The mechanisms by which intrinsically disordered proteins engage in rapid and highly selective binding is a subject of considerable interest and represents a central paradigm to nuclear pore complex (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.

PMID:
26456112
PMCID:
PMC4622936
DOI:
10.1016/j.cell.2015.09.047
[Indexed for MEDLINE]
Free PMC Article

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