title: A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors.
abstract: Despite their physiological importance, selective interactions between nuclear receptors (NRs) and their cofactors are poorly understood. Here, we describe a novel signature motif (F/YSXXLXXL/Y) in the developmental regulator BCL11A that facilitates its selective interaction with members of the NR2E/F subfamily. Two copies of this motif (named here as RID1 and RID2) permit BCL11A to bind COUP-TFs (NR2F1;NR2F2;NR2F6) and Tailless/TLX (NR2E1), whereas RID1, but not RID2, binds PNR (NR2E3). We confirmed the existence of endogenous BCL11A/TLX complexes in mouse cortex tissue. No interactions of RID1 and RID2 with 20 other ligand-binding domains from different NR subtypes were observed. We show that RID1 and RID2 are required for BCL11A-mediated repression of endogenous γ-globin gene and the regulatory non-coding transcript Bgl3, and we identify COUP-TFII binding sites within the Bgl3 locus. In addition to their importance for BCL11A function, we show that F/YSXXLXXL/Y motifs are conserved in other NR cofactors. A single FSXXLXXL motif in the NR-binding SET domain protein NSD1 facilitates its interactions with the NR2E/F subfamily. However, the NSD1 motif incorporates features of both LXXLL and FSXXLXXL motifs, giving it a distinct NR-binding pattern in contrast to other cofactors. In summary, our results provide new insights into the selectivity of NR/cofactor complex formation.
authors: Gene Regulation Group, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK, School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK and School of Veterinary Medicine and Science, University of Nottingham, Nottingham NG7 2RD, UK.
authors: Chun Ming
authors: CM
authors: Chan
authors: Joel
authors: J
authors: Fulton
authors: Cristina
authors: C
authors: Montiel-Duarte
authors: Hilary M
authors: HM
authors: Collins
authors: Neetu
authors: N
authors: Bharti
authors: Frances R
authors: FR
authors: Wadelin
authors: Paula M
authors: PM
authors: Moran
authors: Nigel P
authors: NP
authors: Mongan
authors: David M
authors: DM
authors: Heery
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051837:COUP Transcription Factor II / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D055545:gamma-Globins / Q000235:genetics
chemical_list: C486563:BCL11A protein, human; D051837:COUP Transcription Factor II; D002352:Carrier Proteins; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D012097:Repressor Proteins; D055545:gamma-Globins
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