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Title: Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Abstract

The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.

Authors:
 [1];  [2];  [2];  [2];  [3];  [4];  [2];  [5]
+ Show Author Affiliations
  1. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States). Lab. of Structural Sciences; Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Autophagy Research Center
  2. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States). Lab. of Structural Sciences
  3. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology
  4. Univ. of California, Riverside, CA (United States). Dept. of Cell Biology and Neuroscience
  5. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States). Lab. of Structural Sciences; Chinese Academy of Sciences (CAS), Shanghai (China). Shanghai Inst. of Materia Medica. Key Lab. of Receptor Research. Van Andel Research Inst.-Shanghai Inst. of Materia Medica (VARI/SIMM) Center
Publication Date:
Research Org.:
Van Andel Research Inst. (VARI), Grand Rapids, MI (United States); Chinese Academy of Sciences (CAS), Shanghai (China)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Michigan Economic Development Corporation (United States); Michigan Technology Tri-Corridor (United States); Jay and Betty Van Andel Foundation (United States); Ministry of Science and Technology (China)
Contributing Org.:
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States); Univ. of California, Riverside, CA (United States)
OSTI Identifier:
1229906
Grant/Contract Number:  
DK071662; NS070981; NS088095; GM102545; GM104212; 085P1000817; 2012ZX09301001; 2012CB910403; 2013CB910600; XDB08020303; 2013ZX09507001
Resource Type:
Accepted Manuscript
Journal Name:
Genes & Development
Additional Journal Information:
Journal Volume: 29; Journal Issue: 4; Journal ID: ISSN 0890-9369
Publisher:
Cold Springs Harbor Press
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; COUP; PNR; SHP; TLX

Citation Formats

Zhi, Xiaoyong, Zhou, X. Edward, He, Yuanzheng, Searose-Xu, Kelvin, Zhang, Chun-Li, Tsai, Chih-Cheng, Melcher, Karsten, and Xu, H. Eric. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. United States: N. p., 2015. Web. doi:10.1101/gad.254904.114.
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Zhi, Xiaoyong, Zhou, X. Edward, He, Yuanzheng, Searose-Xu, Kelvin, Zhang, Chun-Li, Tsai, Chih-Cheng, Melcher, Karsten, & Xu, H. Eric. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. United States. https://doi.org/10.1101/gad.254904.114
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Zhi, Xiaoyong, Zhou, X. Edward, He, Yuanzheng, Searose-Xu, Kelvin, Zhang, Chun-Li, Tsai, Chih-Cheng, Melcher, Karsten, and Xu, H. Eric. Sun . "Structural basis for corepressor assembly by the orphan nuclear receptor TLX". United States. https://doi.org/10.1101/gad.254904.114. https://www.osti.gov/servlets/purl/1229906.
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@article{osti_1229906,
title = {Structural basis for corepressor assembly by the orphan nuclear receptor TLX},
author = {Zhi, Xiaoyong and Zhou, X. Edward and He, Yuanzheng and Searose-Xu, Kelvin and Zhang, Chun-Li and Tsai, Chih-Cheng and Melcher, Karsten and Xu, H. Eric},
abstractNote = {The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.},
doi = {10.1101/gad.254904.114},
journal = {Genes & Development},
number = 4,
volume = 29,
place = {United States},
year = {Sun Feb 15 00:00:00 EST 2015},
month = {Sun Feb 15 00:00:00 EST 2015}
}
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Journal Article:
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https://doi.org/10.1101/gad.254904.114
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Cited by: 17 works
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Figures / Tables:

Figure 1 Figure 1: Structural analysis of the hTLX–Atro box complex. (A) Binding of hTLX wild type (WT) and BD (the mutant used in crystallization) to Atrophin peptides. His6MBP-fused hTLX LBD-WT (residues 182–385) and hTLX LBD-BD (residues 182–385, K257R/ N259T/K260L/C338V) were used in AlphaScreen assays against three biotinylated peptides derived from Atrophinmore » proteins. Error bars indicate SD (n = 3). The sequences of peptides are listed, with the Atro box sequence boxed. (B) A ribbon model of hTLX (molecule A) (apo; green), hTLX (molecule C) (dAtro complex; pink), and their superposition. (C) Representative Fo - Fc electron density omit map contoured at 1.0 σ for peptide dAtro (complex C) (red). dAtrophin amino acids involved in hTLX binding are highlighted in yellow, labeled in red, and underlined. dAtrophin-binding amino acids in hTLX are labeled in black and underlined. They are contributed to by helices H3 and H12, which are labeled in black and boxed, and also by the loop between H11 and H12. (D) Close-up presentation of the hTLX/Atrophin interface. hTLX amino acids involved in the interaction are marked by a pink transparent surface, labeled in black, and underlined. dAtrophin amino acids involved in the interaction are marked in yellow, labeled in red, and underlined. The black dashed line represents the H bond interaction between hTLX and Atrophin.« less
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    Works referencing / citing this record:

    Co-activator candidate interactions for orphan nuclear receptor NR2E1
    text, January 2017

    • Corso-Díaz, Ximena; De Leeuw, Charles N.; Alonso, Vivian
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    • DOI: 10.14288/1.0362086

    Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor
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    Co-activator candidate interactions for orphan nuclear receptor NR2E1
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    Co-activator candidate interactions for orphan nuclear receptor NR2E1
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    Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor
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    • Dueva, Evgenia; Singh, Kriti; Kalyta, Anastasia
    • Multidisciplinary Digital Publishing Institute
    • DOI: 10.14288/1.0379429

    TLX—Its Emerging Role for Neurogenesis in Health and Disease
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    Crystal structures of MBP fusion proteins: Structures of MBP Fusion Proteins
    journal, January 2016

    Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor
    journal, November 2018

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