Structural mechanism for signal transduction in RXR nuclear receptor heterodimers

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, Andrew I. Shulman, Mark Rance, Patrick R. Griffin, John B. Bruning and Kendall W. Nettles ()
Additional contact information
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9013

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DOI: 10.1038/ncomms9013

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