Dynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release

• Published in: Nature communications 2017-12, Vol.8 (1), p.2215-16, Article 2215
• Main Authors: Warren, Christopher, Matsui, Tsutomu, Karp, Jerome M., Onikubo, Takashi, Cahill, Sean, Brenowitz, Michael, Cowburn, David, Girvin, Mark, Shechter, David
• Format: Article
• Language: English
• Subjects: 631/337/100; 631/45; 631/45/535/1261; 631/535/878/1263; Animals; Binding; Biochemistry; Chaperones; Chromatin; Control; Crystallography, X-Ray; Experiments; Histone Chaperones - metabolism; Histones; Histones - metabolism; Humanities and Social Sciences; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Localization; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; multidisciplinary; NMR; Nuclear magnetic resonance; Nucleoplasmins - metabolism; Nucleosomes - metabolism; Protein Binding; Proteins; Scattering, Small Angle; Science; Science (multidisciplinary); Sedimentation & deposition; Shielding; Small angle X ray scattering; X-ray scattering; Xenopus laevis; Xenopus Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02308-3

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. The histone chaperone nucleoplasmin (Npm) stores histones H2A/H2B in the egg and embryo. Here, the authors use NMR to show that Npm’s intrinsically disordered tail domain controls histone binding at an acidic stretch, which is autoregulated through direct competition with its basic C-terminus.