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J Biol Chem. 2018 Mar 23;293(12):4555-4563. doi: 10.1074/jbc.AC117.001649. Epub 2018 Jan 26.

Thermodynamic characterization of the multivalent interactions underlying rapid and selective translocation through the nuclear pore complex.

Author information

1
From the Laboratory of Cellular and Structural Biology, Rockefeller University, New York, New York 10065.
2
the Departments of Biochemistry and of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, and.
3
the New York Structural Biology Center, New York, New York 10027.
4
From the Laboratory of Cellular and Structural Biology, Rockefeller University, New York, New York 10065, rout@mail.rockefeller.edu.
5
the Departments of Biochemistry and of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, and cowburn@cowburnlab.org.

Abstract

Intrinsically disordered proteins (IDPs) play important roles in many biological systems. Given the vast conformational space that IDPs can explore, the thermodynamics of the interactions with their partners is closely linked to their biological functions. Intrinsically disordered regions of Phe-Gly nucleoporins (FG Nups) that contain multiple phenylalanine-glycine repeats are of particular interest, as their interactions with transport factors (TFs) underlie the paradoxically rapid yet also highly selective transport of macromolecules mediated by the nuclear pore complex. Here, we used NMR and isothermal titration calorimetry to thermodynamically characterize these multivalent interactions. These analyses revealed that a combination of low per-FG motif affinity and the enthalpy-entropy balance prevents high-avidity interaction between FG Nups and TFs, whereas the large number of FG motifs promotes frequent FG-TF contacts, resulting in enhanced selectivity. Our thermodynamic model underlines the importance of functional disorder of FG Nups. It helps explain the rapid and selective translocation of TFs through the nuclear pore complex and further expands our understanding of the mechanisms of "fuzzy" interactions involving IDPs.

KEYWORDS:

FG Nups/FG repeats; Phe-Gly nucleoporin; avidity; intrinsically disordered protein; isothermal titration calorimetry (ITC); multifunctional protein; multivalent interactions/fuzzy interactions; nuclear magnetic resonance (NMR); nuclear pore; nuclear pore complex; nuclear transport; nuclear transport/NTF2; protein complex; transport; transport factor

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