The nonconserved hinge region and distinct amino-terminal domains of the ROR alpha orphan nuclear receptor isoforms are required for proper DNA bending and ROR alpha-DNA interactions
The nonconserved hinge region and distinct amino-terminal domains of the ROR alpha orphan nuclear receptor isoforms are required for proper DNA bending and ROR alpha-DNA interactions
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ROR α 孤儿核受体亚型的非保守铰链区和独特的氨基末端结构域是正确的 DNA 弯曲和 ROR α-DNA 相互作用所必需的
DOI：
10.1128/mcb.15.2.796
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发表时间：
1995
影响因子：
5.3
通讯作者：
V. Giguère
中科院分区：
文献类型：
--
作者：
L. McBroom;G. Flock;V. Giguère
RORα1和RORα2是类固醇-甲状腺-维甲酸受体超家族中一个新成员的两个亚型，由于它们的同源配体尚未确定，因此被认为是孤儿受体。这些假定的受体以前被证明作为单体与DNA识别序列结合，该序列由两个不同的部分组成，一个3‘核受体核心半位点AGGTCA，前面是一个富含5’AT的序列。识别这种二分激素反应元件(RORE)需要锌结合基序和位于DNA结合域(DBD)羧基末端的一组氨基酸残基，这里称为羧基末端延伸。在这份报告中，我们证明了RORα1和RORα2与RORE的结合诱导了大约130度的DNA大弯曲，这可能对受体的功能是重要的。DNA弯曲的总体方向是朝向3‘AGGTCA半位点中心的主要凹槽。位于DBD和假定的配体结合域(LBD)或RORα之间的非保守铰链区的存在是实现最大DNA弯曲的必要条件。RORα蛋白氨基末端结构域(NTD)的大部分缺失不会改变DNA的弯曲角度，但会使DNA弯曲中心5‘相对于完整的RORα诱导的弯曲移动。用NTD缺失的RORα1突变体进行的甲基化干扰研究表明，RORE的5‘AT富含一半的DNA接触点也移动了5’，而3‘AGGTCA半位点的DNA接触点不受影响。这些结果与RORαNTD和非保守铰链区相互定位锌结合基序和RORαDBD的羧基末端延伸以实现与其识别位点的两半正确相互作用的模型是一致的。反式激活研究表明，蛋白质诱导的DNA弯曲和蛋白质-蛋白质相互作用对受体功能都很重要。
ROR alpha 1 and ROR alpha 2 are two isoforms of a novel member of the steroid-thyroid-retinoid receptor superfamily and are considered orphan receptors since their cognate ligand has yet to be identified. These putative receptors have previously been shown to bind as monomers to a DNA recognition sequence composed of two distinct moieties, a 3' nuclear receptor core half-site AGGTCA preceded by a 5' AT-rich sequence. Recognition of this bipartite hormone response element (RORE) requires both the zinc-binding motifs and a group of amino acid residues located at the carboxy-terminal end of the DNA-binding domain (DBD) which is referred to here as the carboxy-terminal extension. In this report, we show that binding of ROR alpha 1 and ROR alpha 2 to the RORE induces a large DNA bend of approximately 130 degrees which may be important for receptor function. The overall direction of the DNA bend is towards the major groove at the center of the 3' AGGTCA half-site. The presence of the nonconserved hinge region which is located between the DBD and the putative ligand-binding domain (LBD) or ROR alpha is required for maximal DNA bending. Deletion of a large portion of the amino-terminal domain (NTD) of the ROR alpha protein does not alter the DNA bend angle but shifts the DNA bend center 5' relative to the bend induced by intact ROR alpha. Methylation interference studies using the NTD-deleted ROR alpha 1 mutant indicate that some DNA contacts in the 5' AT-rich half of the RORE are also shifted 5', while those in the 3' AGGTCA half-site are unaffected. These results are consistent with a model in which the ROR alpha NTD and the nonconserved hinge region orient the zinc-binding motifs and the carboxy-terminal extension of the ROR alpha DBD relative to each other to achieve proper interactions with the two halves of its recognition site. Transactivation studies suggest that both protein-induced DNA bending and protein-protein interactions are important for receptor function.
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DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Leidig,F;Shepard,AR;Zhang,WG;Stelter,A;Cattini,PA;Baxter,JD;Eberhardt,NL
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
56.9
作者：
Thomas E. Wilson;R. E. Paulsen;Kerstien A. Padgett;Jeffrey Milbrandt
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影响因子：
10.5
作者：
NATESAN, S;GILMAN, MZ
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DOI：
--
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
King,IN;deSoyza,T;Catanzaro,DF;Lavin,TN
通讯作者：
Lavin,TN