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Ser-884 Adjacent to the LXXLL Motif of Coactivator TRBP Defines Selectivity for ERs and TRs

Lilly Research Laboratories, Department of Gene Regulation, Bone and Inflammation Research, Eli Lilly & Co., Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. Lan Ko, Department of Gene Regulation, Bone & Inflammation Research, Lilly Corporate Center, Building 98/C, Drop Code 0434, Indianapolis, Indiana 46285. E-mail: kol{at}lilly.com

Ligand-dependent interaction of nuclear receptors and coactivators is a critical step in nuclear receptor-mediated transcriptional regulation. TR-binding protein (TRBP) interacts with nuclear receptors through a single LXXLL motif. Evidence suggested that the sequences flanking the LXXLL motif in a number of coactivators determine receptor selectivity. We performed mutagenesis studies at residues adjacent to the TRBP LXXLL motif and identified S884 of TRBP at the -3 position of the LXXLL motif as a key residue for receptor selectivity. Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERß, TR, and RXR vs. ER. Transient transfection studies further confirmed that the LXXLL-binding affinity correlates with TRBP transcriptional activity. Consistent with the structural modeling, an E380G substitution within ER altered the binding to TRBP mutants, demonstrating the direct contact between TRBP S884 and ER E380, which is a residue that distinguishes receptor subclasses. Furthermore, S884 can be phosphorylated by MAPK in vitro, an event that significantly altered the binding of TRBP to ER and suggests a potential mechanism for regulatory interaction. As the differential recruitment of TRBP to ER and ERß may rely on S884, our finding provides insight into estrogen signaling and may lead to the development of therapeutic receptor-selective peptide antagonists.

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