DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

Abstract

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.

Authors:
 [1];  [2];  [3];  [1];  [4];  [1]
  1. Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States). Integrative Metabolism Program
  2. Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States). Integrative Metabolism Program; Shandong University (China). Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Sciences
  3. University of California, San Diego, La Jolla, CA (United States). Department of Medicine and UCSD DXMS Proteomics Resource
  4. Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center, Biosciences Division
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1422588
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Cancer; Developmental biology; Drug discovery; X-ray crystallography

Citation Formats

Chandra, Vikas, Wu, Dalei, Li, Sheng, Potluri, Nalini, Kim, Youngchang, and Rastinejad, Fraydoon. The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission. United States: N. p., 2017. Web. doi:10.1038/s41467-017-00981-y.
Chandra, Vikas, Wu, Dalei, Li, Sheng, Potluri, Nalini, Kim, Youngchang, & Rastinejad, Fraydoon. The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission. United States. https://doi.org/10.1038/s41467-017-00981-y
Chandra, Vikas, Wu, Dalei, Li, Sheng, Potluri, Nalini, Kim, Youngchang, and Rastinejad, Fraydoon. Wed . "The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission". United States. https://doi.org/10.1038/s41467-017-00981-y. https://www.osti.gov/servlets/purl/1422588.
@article{osti_1422588,
title = {The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission},
author = {Chandra, Vikas and Wu, Dalei and Li, Sheng and Potluri, Nalini and Kim, Youngchang and Rastinejad, Fraydoon},
abstractNote = {Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.},
doi = {10.1038/s41467-017-00981-y},
journal = {Nature Communications},
number = 1,
volume = 8,
place = {United States},
year = {Wed Oct 11 00:00:00 EDT 2017},
month = {Wed Oct 11 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 36 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids.
journal, January 1993

  • Allenby, G.; Bocquel, M. T.; Saunders, M.
  • Proceedings of the National Academy of Sciences, Vol. 90, Issue 1
  • DOI: 10.1073/pnas.90.1.30

Structure of a Biologically Active Estrogen Receptor-Coactivator Complex on DNA
journal, March 2015


The oligomeric structures of plant cryptochromes
journal, May 2020


Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020

  • Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
  • JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
  • DOI: 10.1007/s00775-020-01814-y

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors
journal, February 2012

  • Osz, J.; Brelivet, Y.; Peluso-Iltis, C.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 10
  • DOI: 10.1073/pnas.1118192109

Nuclear receptor full-length architectures: confronting myth and illusion with high resolution
journal, January 2015

  • Rastinejad, Fraydoon; Ollendorff, Vincent; Polikarpov, Igor
  • Trends in Biochemical Sciences, Vol. 40, Issue 1
  • DOI: 10.1016/j.tibs.2014.10.011

Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA
journal, November 2008

  • Chandra, Vikas; Huang, Pengxiang; Hamuro, Yoshitomo
  • Nature, Vol. 456, Issue 7220
  • DOI: 10.1038/nature07413

Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding
journal, October 1994

  • Kurokawa, Riki; DiRenzo, James; Boehm, Marcus
  • Nature, Vol. 371, Issue 6497
  • DOI: 10.1038/371528a0

Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega
journal, January 2011

  • Sievers, Fabian; Wilm, Andreas; Dineen, David
  • Molecular Systems Biology, Vol. 7, Issue 1
  • DOI: 10.1038/msb.2011.75

Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA
journal, November 2008

  • Chandra, Vikas; Huang, Pengxiang; Hamuro, Yoshitomo
  • Nature, Vol. 456, Issue 7220
  • DOI: 10.1038/nature07413

Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings
journal, April 2011

  • Rochel, Natacha; Ciesielski, Fabrice; Godet, Julien
  • Nature Structural & Molecular Biology, Vol. 18, Issue 5
  • DOI: 10.1038/nsmb.2054

Retinoic Acid Actions through Mammalian Nuclear Receptors
journal, September 2013

  • Huang, Pengxiang; Chandra, Vikas; Rastinejad, Fraydoon
  • Chemical Reviews, Vol. 114, Issue 1
  • DOI: 10.1021/cr400161b

Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings
journal, April 2011

  • Rochel, Natacha; Ciesielski, Fabrice; Godet, Julien
  • Nature Structural & Molecular Biology, Vol. 18, Issue 5
  • DOI: 10.1038/nsmb.2054

Structure of a Biologically Active Estrogen Receptor-Coactivator Complex on DNA
journal, March 2015


Structure of the retinoid X receptor α–liver X receptor β (RXRα–LXRβ) heterodimer on DNA
journal, February 2014

  • Lou, Xiaohua; Toresson, Gudrun; Benod, Cindy
  • Nature Structural & Molecular Biology, Vol. 21, Issue 3
  • DOI: 10.1038/nsmb.2778

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors
journal, February 2012

  • Osz, J.; Brelivet, Y.; Peluso-Iltis, C.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 10
  • DOI: 10.1073/pnas.1118192109

Allosteric Controls of Nuclear Receptor Function in the Regulation of Transcription
journal, July 2013


Understanding nuclear receptor form and function using structural biology
journal, October 2013

  • Rastinejad, Fraydoon; Huang, Pengxiang; Chandra, Vikas
  • Journal of Molecular Endocrinology, Vol. 51, Issue 3
  • DOI: 10.1530/jme-13-0173

The RXR heterodimers and orphan receptors
journal, December 1995


The RXR heterodimers and orphan receptors
journal, December 1995


Minimizing Back Exchange in the Hydrogen Exchange-Mass Spectrometry Experiment
journal, September 2012

  • Walters, Benjamin T.; Ricciuti, Alec; Mayne, Leland
  • Journal of The American Society for Mass Spectrometry, Vol. 23, Issue 12
  • DOI: 10.1007/s13361-012-0476-x

Structural Insights into Fibrinogen Dynamics Using Amide Hydrogen/Deuterium Exchange Mass Spectrometry
journal, July 2013

  • Marsh, James J.; Guan, Henry S.; Li, Sheng
  • Biochemistry, Vol. 52, Issue 32
  • DOI: 10.1021/bi4007995

Host ANP32A mediates the assembly of the influenza virus replicase
journal, November 2020


Multidomain integration in the structure of the HNF-4α nuclear receptor complex
journal, March 2013

  • Chandra, Vikas; Huang, Pengxiang; Potluri, Nalini
  • Nature, Vol. 495, Issue 7441
  • DOI: 10.1038/nature11966

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019


Structure of the RXR–RAR DNA-binding complex on the retinoic acid response element DR1
journal, March 2000

  • Rastinejad, Fraydoon; Wagner, Trixie; Zhao, Qiang
  • The EMBO Journal, Vol. 19, Issue 5
  • DOI: 10.1093/emboj/19.5.1045

Structure of the RXR–RAR DNA-binding complex on the retinoic acid response element DR1
journal, March 2000

  • Rastinejad, Fraydoon; Wagner, Trixie; Zhao, Qiang
  • The EMBO Journal, Vol. 19, Issue 5
  • DOI: 10.1093/emboj/19.5.1045

Allosteric Controls of Nuclear Receptor Function in the Regulation of Transcription
journal, July 2013


Minimizing Back Exchange in the Hydrogen Exchange-Mass Spectrometry Experiment
journal, September 2012

  • Walters, Benjamin T.; Ricciuti, Alec; Mayne, Leland
  • Journal of The American Society for Mass Spectrometry, Vol. 23, Issue 12
  • DOI: 10.1007/s13361-012-0476-x

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

  • Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek
  • Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8
  • DOI: 10.1107/S0907444906019949

Nuclear Receptors, RXR, and the Big Bang
journal, March 2014


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Deciphering key features in protein structures with the new ENDscript server
journal, April 2014

  • Robert, Xavier; Gouet, Patrice
  • Nucleic Acids Research, Vol. 42, Issue W1
  • DOI: 10.1093/nar/gku316

Visualizing the Architectures and Interactions of Nuclear Receptors
journal, November 2016

  • Khorasanizadeh, Sepideh; Rastinejad, Fraydoon
  • Endocrinology, Vol. 157, Issue 11
  • DOI: 10.1210/en.2016-1559

Multiplicity generates diversity in the retinoic acid signalling pathways
journal, October 1992


Structure–function relationships in nuclear receptors: the facts
journal, June 2015

  • Moras, Dino; Billas, Isabelle M. L.; Rochel, Natacha
  • Trends in Biochemical Sciences, Vol. 40, Issue 6
  • DOI: 10.1016/j.tibs.2015.03.009

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Cryo-EM structure of the respiratory syncytial virus RNA polymerase
journal, January 2020


Nuclear Receptors, RXR, and the Big Bang
journal, March 2014


Structural integration in hypoxia-inducible factors
journal, August 2015

  • Wu, Dalei; Potluri, Nalini; Lu, Jingping
  • Nature, Vol. 524, Issue 7565
  • DOI: 10.1038/nature14883

Stock-based detection of protein oligomeric states in jsPISA
journal, April 2015


Characterization of the Interaction between Retinoic Acid Receptor/Retinoid X Receptor (RAR/RXR) Heterodimers and Transcriptional Coactivators through Structural and Fluorescence Anisotropy Studies
journal, November 2004

  • Pogenberg, Vivian; Guichou, Jean-François; Vivat-Hannah, Valérie
  • Journal of Biological Chemistry, Vol. 280, Issue 2
  • DOI: 10.1074/jbc.M409302200

Structure of the retinoid X receptor α–liver X receptor β (RXRα–LXRβ) heterodimer on DNA
journal, February 2014

  • Lou, Xiaohua; Toresson, Gudrun; Benod, Cindy
  • Nature Structural & Molecular Biology, Vol. 21, Issue 3
  • DOI: 10.1038/nsmb.2778

Structural Insights into Fibrinogen Dynamics Using Amide Hydrogen/Deuterium Exchange Mass Spectrometry
journal, July 2013

  • Marsh, James J.; Guan, Henry S.; Li, Sheng
  • Biochemistry, Vol. 52, Issue 32
  • DOI: 10.1021/bi4007995

Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice
journal, April 2011

  • Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.
  • Endocrinology, Vol. 152, Issue 6
  • DOI: 10.1210/en.2010-0941

Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding
journal, October 1994

  • Kurokawa, Riki; DiRenzo, James; Boehm, Marcus
  • Nature, Vol. 371, Issue 6497
  • DOI: 10.1038/371528a0

Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega
journal, January 2011

  • Sievers, Fabian; Wilm, Andreas; Dineen, David
  • Molecular Systems Biology, Vol. 7, Issue 1
  • DOI: 10.1038/msb.2011.75

RAR and RXR modulation in cancer and metabolic disease
journal, October 2007

  • Altucci, Lucia; Leibowitz, Mark D.; Ogilvie, Kathleen M.
  • Nature Reviews Drug Discovery, Vol. 6, Issue 10
  • DOI: 10.1038/nrd2397

Stock-based detection of protein oligomeric states in jsPISA
journal, April 2015


Structural integration in hypoxia-inducible factors
journal, August 2015

  • Wu, Dalei; Potluri, Nalini; Lu, Jingping
  • Nature, Vol. 524, Issue 7565
  • DOI: 10.1038/nature14883

Visualizing the Architectures and Interactions of Nuclear Receptors
journal, November 2016

  • Khorasanizadeh, Sepideh; Rastinejad, Fraydoon
  • Endocrinology, Vol. 157, Issue 11
  • DOI: 10.1210/en.2016-1559

Response to Moras et al.
journal, June 2015

  • Rastinejad, Fraydoon; Ollendorff, Vincent; Polikarpov, Igor
  • Trends in Biochemical Sciences, Vol. 40, Issue 6
  • DOI: 10.1016/j.tibs.2015.03.008

Structure–function relationships in nuclear receptors: the facts
journal, June 2015

  • Moras, Dino; Billas, Isabelle M. L.; Rochel, Natacha
  • Trends in Biochemical Sciences, Vol. 40, Issue 6
  • DOI: 10.1016/j.tibs.2015.03.009

Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice
journal, April 2011

  • Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.
  • Endocrinology, Vol. 152, Issue 6
  • DOI: 10.1210/en.2010-0941

Nuclear receptor full-length architectures: confronting myth and illusion with high resolution
journal, January 2015

  • Rastinejad, Fraydoon; Ollendorff, Vincent; Polikarpov, Igor
  • Trends in Biochemical Sciences, Vol. 40, Issue 1
  • DOI: 10.1016/j.tibs.2014.10.011

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Multidomain integration in the structure of the HNF-4α nuclear receptor complex
journal, March 2013

  • Chandra, Vikas; Huang, Pengxiang; Potluri, Nalini
  • Nature, Vol. 495, Issue 7441
  • DOI: 10.1038/nature11966

Works referencing / citing this record:

Intrinsic Disorder in Nuclear Receptor Amino Termini: From Investigational Challenge to Therapeutic Opportunity
journal, January 2019

  • Shamilov, Rambon; Aneskievich, Brian J.
  • Nuclear Receptor Research, Vol. 6
  • DOI: 10.32527/2019/101417

Integrating Thyroid Hormone Signaling in Hypothalamic Control of Metabolism: Crosstalk Between Nuclear Receptors
journal, July 2018

  • Kouidhi, Soumaya; Clerget-Froidevaux, Marie-Stéphanie
  • International Journal of Molecular Sciences, Vol. 19, Issue 7
  • DOI: 10.3390/ijms19072017

Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus
journal, November 2019


Natural helix 9 mutants of PPARγ differently affect its transcriptional activity
journal, February 2019


Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus
journal, November 2019


Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains
journal, August 2018