Thyroid hormone-independent interaction between the thyroid hormone receptor beta 2 amino terminus and coactivators

Thyroid hormone receptors (TRs) mediate hormone action by binding to DNA re sponse elements (TREs) and either activating or repressing gene expression in the presence of ligand, T-3. Coactivator recruitment to the AF-2 region of TR in the presence of T-3 is central to this process. The different TR i soforms, TR-beta 1, TR-beta 2, and TR-alpha 1, share strong homology in the ir DNA- and ligand-binding domains but differ in their amino-terminal domai ns. Because TR-beta 2 exhibits greater T-3-independent activation on TREs t han other TR isoforms, we wanted to determine whether coactivators bound to TR-beta 2 in the absence of ligand, Our results show that TR-beta 2, unlik e TR-beta 1 or TR-alpha 1, is able to bind certain coactivators (CBP, SRC-1 , and pCIP) in the absence of T-3 through a domain which maps to the amino- terminal half of its A/B domain. This interaction is specific for certain c oactivators, as TR-beta 2 does not interact with other co-factors (p120 or the CBP-associated factor (pCAF)) in the absence of T-3, The minimal TR-bet a 2 domain for coactivator binding is aa 21-50, although aa 1-50 are requir ed for the full functional response. Thus, isoform specific regulation by T Rs may involve T-3-independent coactivator recruitment to the transcription complex via the AF-1 domain.