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

Chandra, Vikas; Wu, Dalei; Li, Sheng; Potluri, Nalini; Kim, Youngchang; Rastinejad, Fraydoon

doi:10.1038/s41467-017-00981-y

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

Journal Article · Wed Oct 11 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/s41467-017-00981-y· OSTI ID:1422588

Chandra, Vikas ^[1]; Wu, Dalei ^[2]; Li, Sheng ^[3]; Potluri, Nalini ^[1]; Kim, Youngchang ^[4]; Rastinejad, Fraydoon ^[1]

Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States). Integrative Metabolism Program
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
University of California, San Diego, La Jolla, CA (United States). Department of Medicine and UCSD DXMS Proteomics Resource
Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center, Biosciences Division

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1422588

Journal Information:: Nature Communications, Vol. 8, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 36 works

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