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首页> 外文期刊>Molecular and Cellular Biology >The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation.
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The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation.

机译：甲状腺激素和视黄酸受体中保守的第九个C端七联体通过影响异二聚体而不是同二聚体的形成来介导多种应答。

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The receptors for thyroid hormone (T3R), all-trans-retinoic acid (RAR), and 9-cis-retinoic acid (RXR) bind DNA response elements as homo- and heterodimers. The ligand-binding domains of these receptors contain nine conserved heptads proposed to play a role in dimerization. Mutant receptors with changes in the first or last hydrophobic amino acids in the highly conserved ninth heptad of chick T3R alpha [cT3R alpha(L365R) and cT3R(L372R)] and human RAR alpha (hRAR alpha) [hRAR(M377R) and hRAR(L384R)] reveal that this heptad is essential for certain heterodimeric interactions and for diverse functional activities. Without ligands, wild-type receptors form both homodimers and heterodimers, while these mutants form only homodimers. Surprisingly, the cognate ligand for each mutant enables heterodimer formation between cT3R(L365R) and RAR or RXR and between hRAR(M377R) and T3R or RXR. Both cT3R(L365R) and hRAR(M377R) mediate ligand-dependent transcriptional regulation. However, unlike the wild-type receptor, non-ligand-associated cT3R(L365R) does not suppress the basal activity of certain promoters containing thyroid hormone response elements, suggesting that this silencing effect of T3R is mediated by unliganded heterodimers of T3R and endogenous RXR or related factors. Heterodimerization is also necessary for the strong ligand-independent inhibition between T3R and RAR on a common response element, since the ninth-heptad mutants function as poor inhibitors. However, with a T3R-specific response element, hRAR(M377R) acts as a retinoic acid-dependent inhibitor of cT3R, indicating the importance of heterodimerization for this inhibition. Our studies also suggest that the ninth heptad is necessary for the dominant inhibition of wild-type T3Rs by mutant T3Rs, as has been found for the thyroid hormone-resistant syndrome in humans. Thus, the ninth heptad repeat is required for heterodimerization, suppression of basal promoter activity, and dominant negative effects of T3R and RAR. Lastly, the finding that cT3R(L365R) and hRAR(M377R) require ligands for heterodimer formation also raises the possibility that heterodimeric interactions are mediated by the ninth heptad without ligands but by a second region of these receptors with ligands.
机译：甲状腺激素（T3R），全反式视黄酸（RAR）和9-顺式视黄酸（RXR）的受体将DNA反应元件结合为同二聚体和异二聚体。这些受体的配体结合域包含九个保守的七聚体，被提议在二聚作用中发挥作用。高度保守的雏鸡T3R alpha [cT3R alpha（L365R）和cT3R（L372R）]和人RAR alpha（hRAR alpha）[hRAR（M377R）和hRAR（ L384R）]揭示了该七肽对于某些异二聚体相互作用和多种功能活性是必不可少的。没有配体，野生型受体既形成同二聚体又形成异二聚体，而这些突变体仅形成同二聚体。令人惊讶地，每个突变体的同源配体使得能够在cT3R（L365R）与RAR或RXR之间以及在hRAR（M377R）与T3R或RXR之间形成异二聚体。 cT3R（L365R）和hRAR（M377R）都介导配体依赖性转录调控。但是，与野生型受体不同，非配体相关的cT3R（L365R）不会抑制某些含有甲状腺激素反应元件的启动子的基础活性，这表明T3R的这种沉默作用是由T3R的非配体异源二聚体和内源性RXR介导的或相关因素。异二聚化对于T3R和RAR之间在共同应答元件上的强不依赖配体的抑制作用也是必需的，因为第九个七聚体突变体起着弱抑制剂的作用。但是，具有T3R特异性应答元件，hRAR（M377R）充当cT3R的视黄酸依赖性抑制剂，表明异二聚化对此抑制作用的重要性。我们的研究还表明，第九个七肽对于突变T3R显性抑制野生型T3R是必需的，正如人类甲状腺激素抵抗综合征所发现的那样。因此，第九个七肽重复是异源二聚化，抑制基础启动子活性以及T3R和RAR的显性负作用所必需的。最后，发现cT3R（L365R）和hRAR（M377R）需要异源二聚体形成的配体的发现也增加了异源二聚体相互作用是由没有配体的第九个七肽介导的，而是由这些具有配体的受体的第二个区域介导的。

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