Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity
Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity
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DOI：
10.1126/scisignal.aao1520
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发表时间：
2018-07-03
影响因子：
7.3
通讯作者：
Baker, Michael E.
中科院分区：
文献类型：
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作者：
Katsu, Yoshinao;Oka, Kaori;Baker, Michael E.
尽管糖皮质激素、盐皮质激素和孕激素家族的多种类固醇配体结合并调节盐皮质激素受体（MR）的活性，但对这些配体的反应在不同物种之间存在差异。为了了解MR的不同结构域如何参与配体诱导的MR活性的激活或抑制，我们研究了对八种类固醇的反应。（醛固酮、11-脱氧皮质酮、11-脱氧皮质醇、皮质醇、皮质酮、孕酮、19-去甲孕酮和螺内酯），其缺少N末端结构域（NTD）和DNA结合结构域（DBD）。与全长MR相比，一些截短的MR不被类固醇激活，而另一些则需要更高的类固醇浓度才能激活。孕酮、19-去甲孕酮和螺内酯不能激活全长或截短的人、鳄鱼或青蛙MR。然而，在10 nM时，这些类固醇激活全长鸡和斑马鱼MR，而在100 nM时，这些类固醇对截短的鸡MR几乎没有活性，但它们保留了对截短的斑马鱼MR的活性。这表明，通过Nitrestin激活鸡MR的调节存在于NTD中。DBD和斑马鱼MR的存在于铰链LBD。斑马鱼和鸡的MR含有丝氨酸对应于丝氨酸（810）在人类MR，这是所需的孕酮对人类MR的拮抗剂活性，这表明一个以前未知的机制，鸡和斑马鱼的MR的调节restestin激活。这些研究结果表明，孕酮可能是一个生理激活剂的鸡和斑马鱼的MR。
Although multiple steroid ligands of the glucocorticoid, mineralocorticoid, and progestin families bind to and regulate the activity of mineralocorticoid receptors (MRs), the responses to these ligands differ across species. To understand how the different domains of MRs contribute to the ligand-induced activation or inhibition of MR activity, we studied the response to eight steroids (aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone, and spironolactone) of human, chicken, alligator, frog, and zebrafish full-length MRs and truncated MRs, which lacked the N-terminal domain (NTD) and DNA binding domain (DBD). Compared to full-length MRs, some truncated MRs were not activated by the steroids, and others required higher steroid concentrations for activation. Progesterone, 19-norprogesterone, and spironolactone did not activate full-length or truncated human, alligator, or frog MRs. However, at 10 nM, these steroids activated full-length chicken and zebrafish MRs, whereas at 100 nM, these steroids had little activity for truncated chicken MRs, but they retained activity for truncated zebrafish MRs. This suggests that regulation of the activation of the chicken MR by progestin resides in the NTD-DBD and that of the zebrafish MR resides in the hinge-LBD. Zebrafish and chicken MRs contain a serine corresponding to Ser(810) in human MR, which is required for the antagonist activity of progesterone for human MR, suggesting a previously uncharacterized mechanism of regulation of progestin activation of chicken and zebrafish MRs. These findings suggest that progesterone may be a physiological activator of chicken and zebrafish MRs.