The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains.
The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains.
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DOI：
10.1210/mend.15.7.0669
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发表时间：
2001-07
影响因子：
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通讯作者：
R. Cohen;Sabrina Brzostek;Brian W. Kim;Michael Chorev;F. Wondisford;A. Hollenberg
中科院分区：
文献类型：
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作者：
R. Cohen;Sabrina Brzostek;Brian W. Kim;Michael Chorev;F. Wondisford;A. Hollenberg
甲状腺激素受体（TR）和视黄酸受体（RAR）亚型与核辅阻遏物[NCoR（核辅阻遏蛋白）和SMRT（类维生素A和甲状腺激素受体的沉默介体）]相互作用，在缺乏配体的情况下沉默转录。NCoR和SMRT含有C-末端核激素受体（NHR）相互作用结构域，每个结构域都含有共有序列I/L-x-x-I/V-I（CoRNR盒）的变体。我们之前已经证明，TRbeta 1优先与NCoR相互作用，而RAR alpha更喜欢SMRT。在这里，我们证明，这是由于，在一定程度上，一个新的NCoR相互作用域的存在下，称为N3，前面描述的域的上游。类似的结构域不存在于SMRT中。该结构域对TR是特异性的，并且与RAR的相互作用很差。我们的数据表明，两个辅阻遏物相互作用域的存在是必要的充分相互作用与细胞核受体。有趣的是，单独的N3突变特异性地降低了细胞中NCoR与TR的结合，但不降低NCoR-RAR相互作用。此外，虽然SMRT相互作用结构域的确切CoRNR盒序列对于RAR募集SMRT至关重要，但CoRNR盒序列本身并不能解释N2结构域与TRbeta 1的强相互作用。需要远离CoRNR盒序列的额外区域以实现最佳结合。因此，通过已知相互作用结构域中的序列差异和新鉴定的相互作用结构域的存在，NCoR能够优先结合TR β 1。这些偏好在体内辅阻遏物作用中可能是重要的。
The thyroid hormone receptor (TR) and retinoic acid receptor (RAR) isoforms interact with the nuclear corepressors [NCoR (nuclear corepressor protein) and SMRT (silencing mediator for retinoid and thyroid hormone receptors)] in the absence of ligand to silence transcription. NCoR and SMRT contain C-terminal nuclear hormone receptor (NHR) interacting domains that each contain variations of the consensus sequence I/L-x-x-I/V-I (CoRNR box). We have previously demonstrated that TRbeta1 preferentially interacts with NCoR, whereas RARalpha prefers SMRT. Here, we demonstrate that this is due, in part, to the presence of a novel NCoR interacting domain, termed N3, upstream of the previously described domains. An analogous domain is not present in SMRT. This domain is specific for TR and interacts poorly with RAR. Our data suggest that the presence of two corepressor interacting domains are necessary for full interactions with nuclear receptors in cells. Interestingly, mutation of N3 alone specifically decreases binding of NCoR to TR in cells but does not decrease NCoR-RAR interactions. In addition, while the exact CoRNR box sequence of a SMRT interacting domain is critical for recruitment of SMRT by RAR, the CoRNR box sequences themselves do not explain the strong interaction of the N2 domain with TRbeta1. Additional regions distal to the CoRNR box sequence are needed for optimal binding. Thus, through sequence differences in known interacting domains and the presence of a newly identified interacting domain, NCoR is able to preferentially bind TRbeta1. These preferences are likely to be important in corepressor action in vivo.