Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA

Ian Mitchelle S. de Vera, Jie Zheng, Scott Novick, Jinsai Shang, Travis S. Hughes, Richard Brust, Paola Munoz-Tello, William J. Gardner, David P. Marciano, Xiangming Kong, Patrick R. Griffin, Douglas J. Kojetin

Research output: Contribution to journalArticlepeer-review

Abstract

Nuclear receptor (NR) transcription factors bind various coreceptors, small-molecule ligands, DNA response element sequences, and transcriptional coregulator proteins to affect gene transcription. Small-molecule ligands and DNA are known to influence receptor structure, coregulator protein interaction, and function; however, little is known on the mechanism of synergy between ligand and DNA. Using quantitative biochemical, biophysical, and solution structural methods, including 13C-detected nuclear magnetic resonance and hydrogen/deuterium exchange (HDX) mass spectrometry, we show that ligand and DNA cooperatively recruit the intrinsically disordered steroid receptor coactivator-2 (SRC-2/TIF2/GRIP1/NCoA-2) receptor interaction domain to peroxisome proliferator-activated receptor gamma-retinoid X receptor alpha (PPARγ-RXRα) heterodimer and reveal the binding determinants of the complex. Our data reveal a thermodynamic mechanism by which DNA binding propagates a conformational change in PPARγ-RXRα, stabilizes the receptor ligand binding domain dimer interface, and impacts ligand potency and cooperativity in NR coactivator recruitment. de Vera et al. combine biophysical and atomic-resolution solution structural methods to show that ligand and DNA binding to PPARγ-RXRα heterodimer cooperatively enhances recruitment of the SRC-2 coactivator, thereby revealing a complex allosteric communication pathway integrating signals from ligand, DNA, and coactivator.

Original languageEnglish
Pages (from-to)1506-1518.e4
JournalStructure
Volume25
Issue number10
DOIs
StatePublished - Oct 3 2017

Keywords

  • NMR spectroscopy
  • allostery
  • cooperativity
  • hydrogen/deuterium exchange (HDX) mass spectrometry
  • ligand binding
  • nuclear receptor
  • peroxisome proliferator-activated receptor
  • retinoid X receptor
  • stabilization
  • transcription

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