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/me.15.7.1049
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发表时间：
2001-07-01
影响因子：
--
通讯作者：
Hollenberg, AN
中科院分区：
文献类型：
--
作者：
Cohen, RN;Brzostek, S;Hollenberg, AN
甲状腺激素受体（TR）和视黄酸受体（RAR）异构体在缺乏配体的情况下与核辅抑制因子[nor（核辅抑制蛋白）和SMRT（类视黄酸和甲状腺激素受体的沉默介质）]相互作用以沉默转录。NCoR和SMRT含有c端核激素受体（NHR）相互作用结构域，每个结构域都包含共识序列I/L-x-x-I/V-I （CoRNR box）的变异。我们之前已经证明，TR β 1优先与NCoR相互作用，而RAR α更倾向于SMRT。在这里，我们证明这部分是由于在前面描述的结构域的上游存在一种新的NCoR相互作用结构域，称为N3。在SMRT中不存在类似的域。这个结构域是TR特有的，与RAR的相互作用很差。我们的数据表明，两个协同抑制子相互作用域的存在是与细胞中核受体充分相互作用所必需的，有趣的是，N3突变特异性地减少了细胞中NCoR与TR的结合，但不会减少NCoR与rar的相互作用。此外，虽然SMRT相互作用结构域的确切CoRNR box序列对于RAR招募SMRT至关重要，但CoRNR box序列本身并不能解释N2结构域与TR beta1的强相互作用。为了实现最佳结合，还需要在CoRNR盒序列的远端添加其他区域。因此，通过已知相互作用结构域的序列差异和新发现的相互作用结构域的存在，NCoR能够优先结合TR beta1。这些偏好在体内的协同抑制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 TR beta1 preferentially interacts with NCoR, whereas RAR alpha 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 TR beta1. 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 TR beta1. These preferences are likely to be important in corepressor action in vivo.