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The retinoid X receptor binding to the thyroid hormone receptor: relationship with cofactor binding and transcriptional activity.

Transcriptional regulation is mediated by thyroid hormone (tri-iodothyronine, T(3)) receptors (TR), which bind to T(3) response elements as heterodimers with retinoid X receptors (RXR). TR binds to corepressor proteins (CoR) in the absence of T(3), which mediate transcriptional repression and to coactivator proteins (CoA) in the presence of T(3), which mediate transcriptional stimulation, by recruiting additional proteins to the promoter. To determine the relationship between TR functions and cofactor bindings, we selected 13 single-point mutants on the ligand binding domain of TR, of which T(3) bindings were well preserved and created VP16 chimeric receptors. Using mammalian two-hybrid assays, RXR binding in the absence of T(3) was almost abolished for Y406K (helix; H10) and L422R (H11), while it was preserved for most other TR mutants. RXR binding was increased for I280K, V284R (H3), and C309K (H6). Addition of T(3) enhanced RXR binding and T(3) restored the RXR binding to Y406K but not to L422R. CoR binding was reduced for P214R, W219K (H1), R316H (H6), D366R (H9), and M423A (H11) in addition to the mutants of which RXR binding was affected, and CoA binding was impaired for I280K, V284R (H3), C309K (H6), and E457K (H12), indicating that sites for CoR, CoA, and RXR binding partially overlap. CoR binding was well correlated with T(3)-independent transcriptional regulation and CoA binding was well correlated with T(3)-dependent regulation, while RXR binding was not correlated with any of these functions among TR mutants, suggesting that transcriptional regulation by TR is mainly mediated by an exchange of CoRs and CoAs.