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

Vikas Chandra, Dalei Wu, Sheng Li, Nalini Potluri, Youngchang Kim and Fraydoon Rastinejad ()
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Vikas Chandra: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute
Dalei Wu: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute
Sheng Li: University of California, San Diego
Nalini Potluri: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute
Youngchang Kim: Structural Biology Center, Biosciences Division, Argonne National Laboratory
Fraydoon Rastinejad: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00981-y

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