TY - JOUR
T1 - Structural mechanism for signal transduction in RXR nuclear receptor heterodimers
AU - Kojetin, Douglas J.
AU - Matta-Camacho, Edna
AU - Hughes, Travis S.
AU - Srinivasan, Sathish
AU - Nwachukwu, Jerome C.
AU - Cavett, Valerie
AU - Nowak, Jason
AU - Chalmers, Michael J.
AU - Marciano, David P.
AU - Kamenecka, Theodore M.
AU - Shulman, Andrew I.
AU - Rance, Mark
AU - Griffin, Patrick R.
AU - Bruning, John B.
AU - Nettles, Kendall W.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/8/20
Y1 - 2015/8/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84939817933&partnerID=8YFLogxK
U2 - 10.1038/ncomms9013
DO - 10.1038/ncomms9013
M3 - Article
C2 - 26289479
AN - SCOPUS:84939817933
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 8013
ER -