A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors

Chan, Chun Ming and Fulton, Joel and Montiel-Duarte, Cristina and Collins, Hilary M. and Bharti, Neetu and Wadelin, Frances R. and Moran, Paula M. and Mongan, Nigel P. and Heery, David M. (2013) A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors. Nucleic Acids Research, 41 (21). pp. 9663-9679. ISSN 1362-4962

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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.

Item Type: Article
Additional Information: This article has been accepted for publication in Nucleic Acids Research published by Oxford University Press.
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Identification Number: https://doi.org/10.1093/nar/gkt761
Depositing User: Mongan, Nigel
Date Deposited: 03 Jul 2015 08:23
Last Modified: 21 Sep 2016 01:49
URI: http://eprints.nottingham.ac.uk/id/eprint/29027

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