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Structural mechanism for signal transduction in RXR nuclear receptor heterodimers

Author

Listed:
  • Douglas J. Kojetin

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Edna Matta-Camacho

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Travis S. Hughes

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Sathish Srinivasan

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Jerome C. Nwachukwu

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Valerie Cavett

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Jason Nowak

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Michael J. Chalmers

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • David P. Marciano

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Theodore M. Kamenecka

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • Andrew I. Shulman

    (University of Texas Southwestern Medical Center
    Present address: Division of Pediatric Rheumatology, Children's Hospital of Orange County, Department of Pediatrics, University of California Irvine, Irvine, California 92697, USA)

  • Mark Rance

    (Biochemistry and Microbiology, University of Cincinnati)

  • Patrick R. Griffin

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

  • John B. Bruning

    (School of Biological Sciences, The University of Adelaide)

  • Kendall W. Nettles

    (The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA)

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.

Suggested Citation

  • Douglas J. Kojetin & Edna Matta-Camacho & Travis S. Hughes & Sathish Srinivasan & Jerome C. Nwachukwu & Valerie Cavett & Jason Nowak & Michael J. Chalmers & David P. Marciano & Theodore M. Kamenecka &, 2015. "Structural mechanism for signal transduction in RXR nuclear receptor heterodimers," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9013
    DOI: 10.1038/ncomms9013
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