Makowski Anita, Brzostek Sabrina, Cohen Ronald N, Hollenberg Anthony N
Thyroid Unit, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2003 Feb;17(2):273-86. doi: 10.1210/me.2002-0310.
The thyroid hormone receptor (TR) recruits the nuclear corepressors, nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT), to target DNA elements in the absence of ligand. While the TR preferentially recruits NCoR, the mechanism remains unclear. The corepressors interact with the TR via interacting domains (IDs) present in their C terminus which contain a conserved motif termed a CoRNR box. Despite their similarity, the corepressor IDs allow for nuclear receptor specificity. Here we demonstrate that NCoR stabilizes the TR homodimer when bound to DNA by preventing its dissociation from thyroid hormone response elements. This suggests that NCoR acts to hold the repression complex in place on target elements. The TR homodimer recruits NCoR through two of its three IDs, one of which is not present in SMRT. This unique ID, N3, contains a CoRNR box but lacks the extended helical motif present in each of the other IDs. Instead, N3 contains an isoleucine just proximal to this motif. This isoleucine is also conserved in N2 but not in the corresponding S2 domain in SMRT. On thyroid hormone response elements and in mammalian cells this residue is critical in both N3 and N2 for high-affinity TR binding. In addition, this residue also controls specificity for the interactions of TR with NCoR. Together these data suggest that the specific recruitment of NCoR by the TR through a unique motif allows for stabilization of the repression complex on target elements.
在没有配体的情况下，甲状腺激素受体（TR）招募核共抑制因子——核受体共抑制因子（NCoR）和视黄酸及甲状腺激素受体沉默介质（SMRT），作用于靶DNA元件。虽然TR优先招募NCoR，但其机制尚不清楚。这些共抑制因子通过其C末端存在的相互作用结构域（ID）与TR相互作用，这些结构域包含一个称为CoRNR框的保守基序。尽管它们相似，但共抑制因子的ID具有核受体特异性。在这里，我们证明，NCoR与DNA结合时可通过防止TR从甲状腺激素反应元件上解离来稳定TR同二聚体。这表明NCoR的作用是将抑制复合物固定在靶元件上。TR同二聚体通过其三个ID中的两个招募NCoR，其中一个ID不存在于SMRT中。这个独特的ID，即N3，包含一个CoRNR框，但缺少其他每个ID中都存在的延伸螺旋基序。相反，N3在这个基序的近端含有一个异亮氨酸。这个异亮氨酸在N2中也保守，但在SMRT的相应S2结构域中不保守。在甲状腺激素反应元件上以及在哺乳动物细胞中，这个残基对于N3和N2与TR的高亲和力结合都至关重要。此外，这个残基还控制TR与NCoR相互作用的特异性。这些数据共同表明，TR通过一个独特基序对NCoR的特异性招募使得抑制复合物能够稳定在靶元件上。
