@article{7dc7cfb162b148018eb8fff4624be62f,
title = "Thermodynamic characterization of the multivalent interactions underlying rapid and selective translocation through the nuclear pore complex",
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 isclosely linked to their biological functions. Intrinsically disordered regions of Phe-Gly nucleoporins (FG Nups) that contain multiple phenylalanine-glycine repeats are of particular interest, astheir interactions with transport factors (TFs) underlie the paradoxically rapid yet also highly selective transportofmacromolecules mediatedbythe 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.",
author = "Ryo Hayama and Samuel Sparks and Hecht, {Lee M.} and Kaushik Dutta and Karp, {Jerome M.} and Cabana, {Christina M.} and Rout, {Michael P.} and David Cowburn and Allewell, {Norma M.}",
note = "Funding Information: This work was supported by National Institutes of Health Grants R01 GM112108, P41 GM109824, and U01 GM098256 (to M. P. R.); R01 GM117212 and S10 OD016305 (to D. C.); and P30 CA013330. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article was selected as one of our Editors{\textquoteright} Picks. This article contains Tables S1–S3, Figs. S1–S11, and supporting information. 1 Both authors contributed equally to this work. 2 Supported by National Institutes of Health Grant T32 GM007288-39. 3Faculty member of the New York Structural Biology Center, supported by NYSTAR. 4To whom correspondence may be addressed: Laboratory of Cellular and Structural Biology, Rockefeller University, 1230 York Ave., New York, NY 10065. Tel.: 212-327-8135; E-mail: rout@mail.rockefeller.edu. 5 To whom correspondence may be addressed: Depts. of Biochemistry and of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461. Tel.: 718-430-8621; E-mail: cowburn@cowburnlab.org. 6The abbreviations used are: IDP, intrinsically disordered protein; TF, transport factor; NPC, nuclear pore complex; ITC, isothermal titration calorimetry; SVD, singular value decomposition; IDR, intrinsically disor- Publisher Copyright: {\textcopyright} 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.",
year = "2018",
month = mar,
day = "23",
doi = "10.1074/jbc.AC117.001649",
language = "English",
volume = "293",
pages = "4555--4563",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "Elsevier Inc.",
number = "12",
}