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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 Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
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. doi: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. doi: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 = {2017},
month = {10}
}

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    Works referencing / citing this record:

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