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Identification of Critical Residues for Heterodimerization within the Ligand-Binding Domain of Retinoid X Receptor

College of Pharmacy (S.-K. L., H.-J.K., J.W.L.) Department of Biology (S.-Y.N., J.S.) Hormone Research Center (J.S., H.-S.C., J.W.L) Chonnam National University Kwangju 500–757, Korea

Nuclear receptors regulate transcription by binding to specific DNA response elements as homodimers or heterodimers with the retinoid X receptors (RXRs). The identity box (I-box), a 40-amino acid region within the ligand-binding domains of RXRs and other nuclear receptors, was recently shown to determine identity in the heterodimeric interactions. Here, we dissected this region in the yeast two-hybrid system by analyzing a series of chimeric receptors between human RXR and rat hepatocyte nuclear factor 4 (HNF4), a distinct member of the nuclear receptor superfamily that prefers homodimerization. We found that the C-terminal 11-amino acid region of the RXR I-box was sufficient to direct chimeric receptors based on the HNF4 ligand-binding domain to heterodimerize with retinoic acid receptors or thyroid hormone receptors. Furthermore, we identified the hRXR amino acids A416 and R421 of the 11-amino acid subregion as most critical determinants of heterodimeric interactions; i.e. mutant HNF4s incorporating only the hRXR A416 or R421 heterodimerized with retinoic acid receptor.

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