Novel signature motifs promote highly selective interactions of the BCL11A co-repressor with the coup-tf, tailless, PNR (NR2E/NR2F) subfamily of orphan nuclear receptors

• Main Author: Chan, Chun Ming
• Published: University of Nottingham 2012
• Subjects: 572.8845
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588078

BCL11A (also known as CTIPl and Evi9) is a Kruppel zinc finger protein that functions as a developmental regulator in haematopoietic and neuronal tissues. It was originally identified as an oncoprotein whose overexpression is associated with acute leukaemia or B-cell lymphoma. Recent genetic studies have linked inactivating mutations in the BCL11A gene to sickle cell disease and B-thalassaemia, and it was subsequently shown that BCL11A protein is a master regulator of foetal haemoglobin switching. A major role of BCL 11 A is its function as a corepressor for DNA binding transcription factors such as NR2F2/COUP-TFII, GATAl and SOX6 transcription factors, and BCL11A appears to act in conjunction with other coregulators such as BCL6, SIRTl, FOG2 and the NuRD complex. In this study, the molecular basis of interaction of BCL11A with the orphan nuclear receptor COUP-TFII (NR2F2) was investigated. Using yeast two hybrid mapping, as well as in vitro and in vivo protein interactions assays, it has been established that BCL11A contains two motifs that are necessary and sufficient for binding to the ligand binding domain of COUP-TFII. These motifs (termed receptor interacting domains RIDl and RID2) are novel variants of the LXXLL and CoRNR box motifs found in other nuclear receptor cofactors. RID 1 and RID2 share the consensus FNSXXLXXLN, but unlike other motifs display highly selective binding to the NR2E/F subfamily of orphan nuclear receptors. I present evidence for functional interactions of RIDl and RID2 with the LBDs ofNR2F2/COUP-TFII, NR2El/TLX and NR2E3/PNR, whereas PNR shows an additional selectivity for RID1. No detectable interactions were observed with more than twenty other LBDs.