@article{ec9cf9d6678240aca2a91f6d1e4893bd,
title = "Dynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release",
abstract = "Nucleoplasmin (Npm) is a highly conserved histone chaperone responsible for the maternal storage and zygotic release of histones H2A/H2B. Npm contains a pentameric N-terminal core domain and an intrinsically disordered C-terminal tail domain. Though intrinsically disordered regions are common among histone chaperones, their roles in histone binding and chaperoning remain unclear. Using an NMR-based approach, here we demonstrate that the Xenopus laevis Npm tail domain controls the binding of histones at its largest acidic stretch (A2) via direct competition with both the C-terminal basic stretch and basic nuclear localization signal. NMR and small-angle X-ray scattering (SAXS) structural analyses allowed us to construct models of both the tail domain and the pentameric complex. Functional analyses demonstrate that these competitive intramolecular interactions negatively regulate Npm histone chaperone activity in vitro. Together these data establish a potentially generalizable mechanism of histone chaperone regulation via dynamic and specific intramolecular shielding of histone interaction sites.",
author = "Christopher Warren and Tsutomu Matsui and Karp, {Jerome M.} and Takashi Onikubo and Sean Cahill and Michael Brenowitz and David Cowburn and Girvin, {Mark E.} and David Shechter",
note = "Funding Information: We thank T. Owen-Hughes and M. Shrogren-Knaak for providing histone cysteine point mutant constructs and W.L. Wang for StrepII-tagged H2A/H2B dimers. We thank C. Schwieters and L. Deshmukh for helpful discussions on PRE-based structural modeling. This work was supported by The American Cancer Society-Robbie Sue Mudd Kidney Cancer Research Scholar Grant (124891-RSG-13-396-01-DMC) and NIH grant R01GM108646 (both to D.S.) and training grants T32GM007491 and F31GM116536 to C.W. J.M.K. was supported by the Einstein MSTP Training Grant (T32 GM007288). The Bruker 600 NMR instrument was purchased using funds from NIH award 1S10OD016305 and is supported by the Albert Einstein College of Medicine. The Inova 600 NMR instrument in the Einstein Structural NMR Resource was purchased using funds from NIH award 1S10RR017998 and NSF award DBI0331934 and is supported by the Albert Einstein College of Medicine. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41467-017-02308-3",
language = "English (US)",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}