N-terminal domain regulates steroid activation of elephant shark glucocorticoid and mineralocorticoid receptors
N-terminal domain regulates steroid activation of elephant shark glucocorticoid and mineralocorticoid receptors
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DOI：
10.1016/j.jsbmb.2021.105845
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发表时间：
2021-03-04
影响因子：
4.1
通讯作者：
Baker, Michael E.
中科院分区：
文献类型：
--
作者：
Katsu, Yoshinao;Shariful, Islam M. D.;Baker, Michael E.
人糖皮质激素受体（GR）和人盐皮质激素受体（MR）的直系同源物首次出现在软骨鱼类中。随后，MR和GR对不同的类固醇产生反应：MR对醛固酮产生反应，GR对皮质醇和皮质酮产生反应。我们报告皮质醇、皮质酮和醛固酮激活全长象鲨GR，而激活象鲨MR的孕酮不激活象鲨GR，然而孕酮抑制类固醇与象鲨GR的结合，但不与人GR结合，这表明象鲨GR与MR的部分功能差异。从象鲨GR缺失N-末端结构域（NTD）（截断GR）减少皮质类固醇的反应，而截断和全长象鲨MR皮质类固醇有类似的反应。交换的NTDs的象鲨GR和MR产生了一个象鲨MR嵌合体全长GR样增加激活皮质类固醇和孕酮相比，全长象鲨MR。象鲨MR NTD融合GR DBD + LBD有类似的激活全长MR，表明MR NTD缺乏GR样NTD活动。我们认为，NTD激活人类GR进化早期GR分歧从MR。
Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and fulllength elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD + LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.