Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Zhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten; Xu, H. Eric

doi:10.1101/gad.254904.114

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Journal Article · Sun Feb 15 04:00:00 EST 2015 · Genes & Development

DOI:https://doi.org/10.1101/gad.254904.114· OSTI ID:1229906

Zhi, Xiaoyong ^[1]; Zhou, X. Edward ^[2]; He, Yuanzheng ^[2]; Searose-Xu, Kelvin ^[2]; Zhang, Chun-Li ^[3]; Tsai, Chih-Cheng ^[4]; Melcher, Karsten ^[2]; Xu, H. Eric ^[5]

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
Van Andel Research Inst. (VARI), Grand Rapids, MI (United States). Lab. of Structural Sciences
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Molecular Biology
Univ. of California, Riverside, CA (United States). Dept. of Cell Biology and Neuroscience
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

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.

View Accepted Manuscript (DOE)

Research Organization:: Van Andel Research Inst. (VARI), Grand Rapids, MI (United States); Chinese Academy of Sciences (CAS), Shanghai (China)

Sponsoring Organization:: 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 Organization:: Univ. of Texas Southwestern Medical Center, Dallas, TX (United States); Univ. of California, Riverside, CA (United States)

OSTI ID:: 1229906

Journal Information:: Genes & Development, Journal Name: Genes & Development Journal Issue: 4 Vol. 29; ISSN 0890-9369

Publisher:: Cold Springs Harbor PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (61)

Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family Escher, Pascal; Gouras, Peter; Roduit, Rapha��l Human Mutation, Vol. 30, Issue 3 https://doi.org/10.1002/humu.20858	journal	March 2009
Control of Early Neurogenesis of theDrosophilaBrain by the Head Gap Genestll, otd, ems,andbtd Younossi-Hartenstein, Amelia; Green, Patricia; Liaw, Gwo-Jen Developmental Biology, Vol. 182, Issue 2 https://doi.org/10.1006/dbio.1996.8475	journal	February 1997
The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min Molecules and Cells, Vol. 30, Issue 5 https://doi.org/10.1007/s10059-010-0122-z	journal	August 2010
The Drosophila gene tailless is expressed at the embryonic termini and is a member of the steroid receptor superfamily Pignoni, Francesca; Baldarelli, Richard M.; Steingrimsson, Eirikur Cell, Vol. 62, Issue 1 https://doi.org/10.1016/0092-8674(90)90249-E	journal	July 1990
The nuclear receptor superfamily: The second decade Mangelsdorf, David J.; Thummel, Carl; Beato, Miguel Cell, Vol. 83, Issue 6 https://doi.org/10.1016/0092-8674(95)90199-X	journal	December 1995
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Gene Silencing by Nuclear Orphan Receptors Zhang, Ying; Dufau, Maria L. Nuclear Receptor Coregulators https://doi.org/10.1016/S0083-6729(04)68001-0	book	January 2004
Coactivator and corepressor complexes in nuclear receptor function Xu, Lan; Glass, Christopher K.; Rosenfeld, Michael G. Current Opinion in Genetics & Development, Vol. 9, Issue 2 https://doi.org/10.1016/S0959-437X(99)80021-5	journal	April 1999
Asymmetry in the PPARγ/RXRα Crystal Structure Reveals the Molecular Basis of Heterodimerization among Nuclear Receptors Gampe, Robert T.; Montana, Valerie G.; Lambert, Millard H. Molecular Cell, Vol. 5, Issue 3 https://doi.org/10.1016/S1097-2765(00)80448-7	journal	March 2000
Molecular Recognition of Fatty Acids by Peroxisome Proliferator–Activated Receptors Xu, H. Eric; Lambert, Millard H.; Montana, Valerie G. Molecular Cell, Vol. 3, Issue 3 https://doi.org/10.1016/S1097-2765(00)80467-0	journal	March 1999
TLX: A master regulator for neural stem cell maintenance and neurogenesis Islam, Mohammed M.; Zhang, Chun-Li Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Vol. 1849, Issue 2 https://doi.org/10.1016/j.bbagrm.2014.06.001	journal	February 2015
Nuclear Receptors, RXR, and the Big Bang Evans, Ronald M.; Mangelsdorf, David J. Cell, Vol. 157, Issue 1 https://doi.org/10.1016/j.cell.2014.03.012	journal	March 2014
Structural analysis of nuclear receptors: From isolated domains to integral proteins Brélivet, Yann; Rochel, Natacha; Moras, Dino Molecular and Cellular Endocrinology, Vol. 348, Issue 2 https://doi.org/10.1016/j.mce.2011.08.015	journal	January 2012
The Tailless Root of Glioma: Cancer Stem Cells Xie, Qi; Flavahan, William A.; Bao, Shideng Cell Stem Cell, Vol. 15, Issue 2 https://doi.org/10.1016/j.stem.2014.07.004	journal	August 2014
Advances in our structural understanding of orphan nuclear receptors Gallastegui, Nerea; Mackinnon, Jonathan A. G.; Fletterick, Robert J. Trends in Biochemical Sciences, Vol. 40, Issue 1 https://doi.org/10.1016/j.tibs.2014.11.002	journal	January 2015
Krüppel requirement for knirps enhancement reflects overlapping gap gene activities in the Drosophila embryo Pankratz, Michael J.; Hoch, Michael; Seifert, Eveline Nature, Vol. 341, Issue 6240 https://doi.org/10.1038/341337a0	journal	September 1989
Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx Yu, Ruth T.; McKeown, Michael; Evans, Ronald M. Nature, Vol. 370, Issue 6488 https://doi.org/10.1038/370375a0	journal	August 1994
Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα Xu, H. Eric; Stanley, Thomas B.; Montana, Valerie G. Nature, Vol. 415, Issue 6873 https://doi.org/10.1038/415813a	journal	February 2002
Atrophin recruits HDAC1/2 and G9a to modify histone H3K9 and to determine cell fates Wang, Lei; Charroux, Bernard; Kerridge, Stephen EMBO reports, Vol. 9, Issue 6 https://doi.org/10.1038/embor.2008.67	journal	May 2008
Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors Wang, Zhulun; Benoit, Gérard; Liu, Jinsong Nature, Vol. 423, Issue 6939 https://doi.org/10.1038/nature01645	journal	May 2003
Expression and function of orphan nuclear receptor TLX in adult neural stem cells Shi, Yanhong; Chichung Lie, D.; Taupin, Philippe Nature, Vol. 427, Issue 6969 https://doi.org/10.1038/nature02211	journal	January 2004
A role for adult TLX-positive neural stem cells in learning and behaviour Zhang, Chun-Li; Zou, Yuhua; He, Weimin Nature, Vol. 451, Issue 7181 https://doi.org/10.1038/nature06562	journal	January 2008
Rere controls retinoic acid signalling and somite bilateral symmetry Vilhais-Neto, Gonçalo C.; Maruhashi, Mitsuji; Smith, Karen T. Nature, Vol. 463, Issue 7283 https://doi.org/10.1038/nature08763	journal	February 2010
Super-resolution biomolecular crystallography with low-resolution data Schröder, Gunnar F.; Levitt, Michael; Brunger, Axel T. Nature, Vol. 464, Issue 7292 https://doi.org/10.1038/nature08892	journal	April 2010
Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis Davis, Shaun M.; Thomas, Amanda L.; Nomie, Krystle J. Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms4177	journal	February 2014
Improved low-resolution crystallographic refinement with Phenix and Rosetta DiMaio, Frank; Echols, Nathaniel; Headd, Jeffrey J. Nature Methods, Vol. 10, Issue 11 https://doi.org/10.1038/nmeth.2648	journal	September 2013
Structure of Rev-erbα bound to N-CoR reveals a unique mechanism of nuclear receptor–co-repressor interaction Phelan, Caroline A.; Gampe, Robert T.; Lambert, Millard H. Nature Structural & Molecular Biology, Vol. 17, Issue 7 https://doi.org/10.1038/nsmb.1860	journal	June 2010
A cell cycle-dependent co-repressor mediates photoreceptor cell-specific nuclear receptor function Takezawa, Shinichiro; Yokoyama, Atsushi; Okada, Maiko The EMBO Journal, Vol. 26, Issue 3 https://doi.org/10.1038/sj.emboj.7601548	journal	January 2007
Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner Li, Y.; Choi, M.; Suino, K. Proceedings of the National Academy of Sciences, Vol. 102, Issue 27 https://doi.org/10.1073/pnas.0501204102	journal	June 2005
Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation Sun, GuoQiang; Yu, Ruth T.; Evans, Ronald M. Proceedings of the National Academy of Sciences, Vol. 104, Issue 39 https://doi.org/10.1073/pnas.0704089104	journal	September 2007
Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis Sanyal, S.; Bavner, A.; Haroniti, A. Proceedings of the National Academy of Sciences, Vol. 104, Issue 40 https://doi.org/10.1073/pnas.0706736104	journal	September 2007
The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1 Sablin, E. P.; Woods, A.; Krylova, I. N. Proceedings of the National Academy of Sciences, Vol. 105, Issue 47 https://doi.org/10.1073/pnas.0808936105	journal	November 2008
Structural insights into gene repression by the orphan nuclear receptor SHP Zhi, X.; Zhou, X. E.; He, Y. Proceedings of the National Academy of Sciences, Vol. 111, Issue 2 https://doi.org/10.1073/pnas.1322827111	journal	December 2013
Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors Xu, H. E.; Lambert, M. H.; Montana, V. G. Proceedings of the National Academy of Sciences, Vol. 98, Issue 24 https://doi.org/10.1073/pnas.241410198	journal	November 2001
The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong Journal of Biological Chemistry, Vol. 286, Issue 4 https://doi.org/10.1074/jbc.M110.168740	journal	November 2010
Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes Zhi, Xiaoyong; Zhou, X. Edward; Melcher, Karsten Journal of Biological Chemistry, Vol. 287, Issue 7 https://doi.org/10.1074/jbc.M111.315242	journal	December 2011
Structural Basis for the Cell-specific Activities of the NGFI-B and the Nurr1 Ligand-binding Domain Flaig, Ralf; Greschik, Holger; Peluso-Iltis, Carole Journal of Biological Chemistry, Vol. 280, Issue 19 https://doi.org/10.1074/jbc.M413175200	journal	May 2005
A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP Bavner, A.; Johansson, L.; Toresson, G. EMBO reports, Vol. 3, Issue 5 https://doi.org/10.1093/embo-reports/kvf087	journal	May 2002
Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression Boulias, K. Nucleic Acids Research, Vol. 32, Issue 20 https://doi.org/10.1093/nar/gkh947	journal	November 2004
Histone deacetylase-associating Atrophin proteins are nuclear receptor corepressors Wang, L. Genes & Development, Vol. 20, Issue 5 https://doi.org/10.1101/gad.1393506	journal	March 2006
Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Zhang, C. -L. Genes & Development, Vol. 20, Issue 10 https://doi.org/10.1101/gad.1413606	journal	May 2006
The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone Liu, Hai-Kun; Belz, Thorsten; Bock, Dagmar Genes & Development, Vol. 22, Issue 18 https://doi.org/10.1101/gad.479308	journal	September 2008
The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation Liu, Hai-Kun; Wang, Ying; Belz, Thorsten Genes & Development, Vol. 24, Issue 7 https://doi.org/10.1101/gad.560310	journal	April 2010
Improved methods for building protein models in electron density maps and the location of errors in these models Jones, T. A.; Zou, J. Y.; Cowan, S. W. Acta Crystallographica Section A Foundations of Crystallography, Vol. 47, Issue 2, p. 110-119 https://doi.org/10.1107/S0108767390010224	journal	March 1991
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
The CCP4 suite programs for protein crystallography No authors listed Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination Brünger, A. T.; Adams, P. D.; Clore, G. M. Acta Crystallographica Section D Biological Crystallography, Vol. 54, Issue 5 https://doi.org/10.1107/S0907444998003254	journal	September 1998
Dual Role of the Drosophila Pattern Gene tailless in Embryonic Termini Steingrímsson, Eiríkur; Pignoni, Francesca; Liaw, Gwo-Jen Science, Vol. 254, Issue 5030 https://doi.org/10.1126/science.1925599	journal	October 1991
Histone Demethylase LSD1 Regulates Neural Stem Cell Proliferation Sun, GuoQiang; Alzayady, Kamil; Stewart, Richard Molecular and Cellular Biology, Vol. 30, Issue 8 https://doi.org/10.1128/MCB.01116-09	journal	April 2010
The Nuclear Receptor TLX Is Required for Gliomagenesis within the Adult Neurogenic Niche Zou, Yuhua; Niu, Wenze; Qin, Song Molecular and Cellular Biology, Vol. 32, Issue 23 https://doi.org/10.1128/MCB.01122-12	journal	December 2012
Transrepressive Function of TLX Requires the Histone Demethylase LSD1 Yokoyama, Atsushi; Takezawa, Shinichiro; Schüle, Roland Molecular and Cellular Biology, Vol. 28, Issue 12 https://doi.org/10.1128/MCB.02030-07	journal	June 2008
A Tale of Tailless Gui, Hongxing; Li, Mei-Ling; Tsai, Chih-Cheng Developmental Neuroscience, Vol. 33, Issue 1 https://doi.org/10.1159/000321585	journal	December 2010
A Transcriptional Silencing Domain in DAX-1 Whose Mutation Causes Adrenal Hypoplasia Congenita Lalli, Enzo; Bardoni, Barbara; Zazopoulos, Emmanuel Molecular Endocrinology, Vol. 11, Issue 13, 1950–1960 https://doi.org/10.1210/me.11.13.1950	journal	December 1997
Drosophila Brakeless Interacts with Atrophin and Is Required for Tailless-Mediated Transcriptional Repression in Early Embryos Haecker, Achim; Qi, Dai; Lilja, Tobias PLoS Biology, Vol. 5, Issue 6 https://doi.org/10.1371/journal.pbio.0050145	journal	May 2007
Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid–Activated Receptor Kruse, Schoen W.; Suino-Powell, Kelly; Zhou, X. Edward PLoS Biology, Vol. 6, Issue 9 https://doi.org/10.1371/journal.pbio.0060227	journal	September 2008
The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation Tan, M. H. Eileen; Zhou, X. Edward; Soon, Fen-Fen PLoS ONE, Vol. 8, Issue 9 https://doi.org/10.1371/journal.pone.0074359	journal	September 2013
The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable Benod, Cindy; Villagomez, Rosa; Filgueira, Carly S. PLoS ONE, Vol. 9, Issue 6 https://doi.org/10.1371/journal.pone.0099440	journal	June 2014
The orphan nuclear receptors at their 25-year reunion Mullican, Shannon E.; DiSpirito, Joanna R.; Lazar, Mitchell A. Journal of Molecular Endocrinology, Vol. 51, Issue 3 https://doi.org/10.1530/JME-13-0212	journal	October 2013
Atrophin Proteins: An Overview of a New Class of Nuclear Receptor Corepressors Wang, Lei; Tsai, Chih-Cheng Nuclear Receptor Signaling, Vol. 6, Issue 1 https://doi.org/10.1621/nrs.06009	journal	January 2008

Cited By (7)

TLX—Its Emerging Role for Neurogenesis in Health and Disease Sobhan, Praveen K.; Funa, Keiko Molecular Neurobiology, Vol. 54, Issue 1 https://doi.org/10.1007/s12035-015-9608-1	journal	January 2016
Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations Fulton, Joel; Mazumder, Bismoy; Whitchurch, Jonathan B. Cell Death & Disease, Vol. 8, Issue 3 https://doi.org/10.1038/cddis.2017.98	journal	March 2017
Co-activator candidate interactions for orphan nuclear receptor NR2E1 Corso-Díaz, Ximena; de Leeuw, Charles N.; Alonso, Vivian BMC Genomics, Vol. 17, Issue 1 https://doi.org/10.1186/s12864-016-3173-5	journal	October 2016
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor Dueva, Evgenia; Singh, Kriti; Kalyta, Anastasia Molecules, Vol. 23, Issue 11 https://doi.org/10.3390/molecules23112967	journal	November 2018
Crystal structures of MBP fusion proteins: Structures of MBP Fusion Proteins Waugh, David S. Protein Science, Vol. 25, Issue 3 https://doi.org/10.1002/pro.2863	journal	January 2016
Co-activator candidate interactions for orphan nuclear receptor NR2E1 Corso-Díaz, Ximena; De Leeuw, Charles N.; Alonso, Vivian BioMed Central https://doi.org/10.14288/1.0362086	text	January 2017
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor Dueva, Evgenia; Singh, Kriti; Kalyta, Anastasia Multidisciplinary Digital Publishing Institute https://doi.org/10.14288/1.0379429	text	January 2019