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:
-
- 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
- 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}
}
Web of Science
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