The quaternary architecture of RARβ-RXRα heterodimer facilitates domain-domain signal transmission

  • Nat Commun. 2017 Oct 11;8(1):868. doi: 10.1038/s41467-017-00981-y.
Vikas Chandra  1 ,  Dalei Wu  1  2 ,  Sheng Li  3 ,  Nalini Potluri  1 ,  Youngchang Kim  4 ,  Fraydoon Rastinejad  5
Affiliations
  • 1. Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, 32827, USA.
  • 2. Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Qingdao, Shandong, 266237, China.
  • 3. Department of Medicine and UCSD DXMS Proteomics Resource, University of California, San Diego, La Jolla, CA, 92023, USA.
  • 4. Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, IL, 60439, USA.
  • 5. Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, 32827, USA. [email protected].
PMID: 29021580 DOI: 10.1038/s41467-017-00981-y
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 β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator Peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARβ 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 heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor β-retinoic X receptor α (RARβ-RXRα) heterodimer bound to DNA, ligands and coactivator Peptides, which shows that NR quaternary architectures are variable.