Structural mechanism for signal transduction in RXR nuclear receptor heterodimers

Nat Commun. 2015 Aug 20;6:8013. doi: 10.1038/ncomms9013.

Abstract

A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR co-operates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-γ, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signalling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signalling pathways into RXR heterodimer-specific responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Gene Expression Regulation / physiology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Protein Conformation
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism*
  • Signal Transduction / physiology*

Substances

  • PPAR gamma
  • Receptors, Thyroid Hormone
  • Retinoid X Receptor alpha

Associated data

  • PDB/4ZO1