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Structural mechanism for signal transduction in RXR nuclear receptor heterodimers

Academic Article
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Overview

related to degree

  • Marciano, David, Ph.D. in Biology, Scripps Research 2010 - 2014

authors

  • Kojetin, Douglas
  • Matta-Camacho, E.
  • Hughes, T. S.
  • Srinivasan, S.
  • Nwachukwu, J. C.
  • Cavett, V.
  • Nowak, J.
  • Chalmers, Michael
  • Marciano, David
  • Kamenecka, Theodore
  • Shulman, A. I.
  • Rance, M.
  • Griffin, Patrick
  • Bruning, John
  • Nettles, Kendall

publication date

  • August 2015

journal

  • Nature Communications  Journal

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)-?, 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.
  • 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.

subject areas

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

PubMed Central ID

  • PMC4547401

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms9013

PubMed ID

  • 26289479
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Additional Document Info

start page

  • 8013

volume

  • 6

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