The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor
Abstract
Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. Here, these findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.
- Authors:
-
- Van Andel Research Inst., Grand Rapids, MI (United States)
- Univ. of Michigan Medical School, Ann Arbor, MI (United States)
- Van Andel Research Inst., Grand Rapids, MI (United States); Rocky Vista Univ., Parker, CO (United States)
- Van Andel Research Inst., Grand Rapids, MI (United States); Grand Valley State Univ., Allendale, MI (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- OSTI Identifier:
- 1022280
- Grant/Contract Number:
- DK071662; DK066202; HL089301; 085P1000817
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 286; Journal Issue: 4; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Crystal Structure; Gene Regulation; Ligand-binding Protein; Nuclear Receptors; Transcription Factors; Ligand Identification; Orphan Nuclear Receptor; Testicular Receptor 4; Transcription Activation; Vitamin A
Citation Formats
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, and Xu, H. Eric. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States: N. p., 2010.
Web. doi:10.1074/jbc.M110.168740.
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, & Xu, H. Eric. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States. https://doi.org/10.1074/jbc.M110.168740
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, and Xu, H. Eric. 2010.
"The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor". United States. https://doi.org/10.1074/jbc.M110.168740. https://www.osti.gov/servlets/purl/1022280.
@article{osti_1022280,
title = {The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor},
author = {Zhou, X. Edward and Suino-Powell, Kelly M. and Xu, Yong and Chan, Cee-Wah and Tanabe, Osamu and Kruse, Schoen W. and Reynolds, Ross and Engel, James Douglas and Xu, H. Eric},
abstractNote = {Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. Here, these findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.},
doi = {10.1074/jbc.M110.168740},
url = {https://www.osti.gov/biblio/1022280},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 4,
volume = 286,
place = {United States},
year = {Tue Nov 09 00:00:00 EST 2010},
month = {Tue Nov 09 00:00:00 EST 2010}
}
Web of Science
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