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.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Autophagy Research Center, eric.xu@vai.org xiaoyong.zhi@utsouthwestern.edu.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: He
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors.forename: Kelvin
authors.initials: K
authors.lastname: Searose-Xu
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Texas 75390, USA;
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology and Neuroscience, University of California at Riverside, Riverside, California 92521, USA;
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Tsai
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Van Andel Research Institute-Shanghai Institute of Materia Medica (VARI/SIMM) Center, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China eric.xu@vai.org xiaoyong.zhi@utsouthwestern.edu.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000818:Animals; D003460:Crystallization; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism; D004331:Drosophila melanogaster / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors / Q000737:chemistry* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear
keywords: COUP; PNR; SHP; TLX