Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.
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.
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Douglas J
DJ
Kojetin
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Edna
E
Matta-Camacho
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Travis S
TS
Hughes
Department of Cancer Biology, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Sathish
S
Srinivasan
Department of Cancer Biology, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Jerome C
JC
Nwachukwu
Department of Cancer Biology, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Valerie
V
Cavett
Department of Cancer Biology, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Jason
J
Nowak
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Michael J
MJ
Chalmers
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
David P
DP
Marciano
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Theodore M
TM
Kamenecka
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Andrew I
AI
Shulman
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Mark
M
Rance
Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Patrick R
PR
Griffin
School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
John B
JB
Bruning
Department of Cancer Biology, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
Kendall W
KW
Nettles
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D047495:PPAR gamma; D011988:Receptors, Thyroid Hormone; D047490:Retinoid X Receptor alpha