Distinct dimerization domains provide antagonist pathways for thyroid hormone receptor action.

Transcriptional regulation by thyroid hormone is mediated through its nuclear receptors, which bind to target response elements as homodimers or as heterodimers with proteins such as retinoid X receptors (RXR). Thyroid hormone response elements exhibit remarkable flexibility in that the receptor binding half-sites can be arranged as direct repeats, inverted repeats, or everted repeats. We report that a limited region at the carboxyl-terminal end of the thyroid hormone receptor differentially contributes to the formation of receptor homo- and heterodimers. The functionally inactive thyroid hormone receptor splicing variant alpha 2, which is altered at the juncture of the homo- and heterodimerization domains, cannot form homodimers. However, alpha 2 can form a heterodimer when bound to half-sites arranged as a direct repeat spaced by 4 base pairs (DR4), but not with other arrangements of response element half-sites. The alpha 2-RXR heterodimer strongly inhibits wild type receptor function mediated by the DR4 element, suggesting that the alpha 2 isoform modulates thyroid hormone action by binding as an antagonist to a subset of response elements.