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; Kendall W. Nettles

doi:10.1038/ncomms9013

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
, Kendall W. Nettles

Research output: Contribution to journal › Article › peer-review

114 Scopus citations

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.

Original language	English
Article number	8013
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9013
State	Published - Aug 20 2015

Funding

We thank David J. Mangelsdorf (the University of Texas Southwestern Medical Center) for discussions related to SCA. Support is acknowledged from an endowed fellowship from the Frenchman’s Creek Women for Cancer Research (S.S.); a fellowship from the Landenberger Foundation (D.P.M.); a NIH Pharmacological Sciences Training Grant (A.I.S); a NIH Medical Scientist Training Program Grant (A.I.S.); a New Investigator Award 1KN-09 from the James and Esther King Biomedical Research Program, Florida Department of Health (D.J.K.); the National Institutes of Health (NIH) National Research Service Award (NRSA) DK097890 (T.S.H.) and Pathway to Independence Award DK103116 (T.S.H.); NIH grants DK101871 (D.J.K.), GM114420 (D.J.K.), GM063855 (M.R.), RR019077 (M.R.), RR027755 (M.R.), MH084512 (P.R.G.), GM084041 (P.R.G.), RR027270 (P.R.G.) and CA132022 (K.W.N.); and the State of Florida for institutional Scripps Florida start-up funds.

Funders	Funder number
1KN-09
S10RR027755
Florida Department of Health
DK097890, RR027755, DK103116, MH084512, RR027270, CA132022, DK101871, GM063855, RR019077, GM084041, GM114420

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10.1038/ncomms9013

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Kojetin, D. J., Matta-Camacho, E., Hughes, T. S., Srinivasan, S., Nwachukwu, J. C., Cavett, V., Nowak, J., Chalmers, M. J., Marciano, D. P., Kamenecka, T. M., Shulman, A. I., Rance, M., Griffin, P. R., Bruning, J. B., & Nettles, K. W. (2015). Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. Nature Communications, 6, Article 8013. https://doi.org/10.1038/ncomms9013

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title = "Structural mechanism for signal transduction in RXR nuclear receptor heterodimers",

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.",

author = "Kojetin, \{Douglas J.\} and Edna Matta-Camacho and Hughes, \{Travis S.\} and Sathish Srinivasan and Nwachukwu, \{Jerome C.\} and Valerie Cavett and Jason Nowak and Chalmers, \{Michael J.\} and Marciano, \{David P.\} and Kamenecka, \{Theodore M.\} and Shulman, \{Andrew I.\} and Mark Rance and Griffin, \{Patrick R.\} and Bruning, \{John B.\} and Nettles, \{Kendall W.\}",

year = "2015",

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doi = "10.1038/ncomms9013",

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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.

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.

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DO - 10.1038/ncomms9013

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8013

ER -

Structural mechanism for signal transduction in RXR nuclear receptor heterodimers

Abstract

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