Structural analysis of the evolution of steroid specificity in the mineralocorticoid and glucocorticoid receptors
Structural analysis of the evolution of steroid specificity in the mineralocorticoid and glucocorticoid receptors
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DOI：
10.1186/1471-2148-7-24
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发表时间：
2007-02-16
影响因子：
3.4
通讯作者：
Ollikainen, Noah
中科院分区：
文献类型：
--
作者：
Baker, Michael E.;Chandsawangbhuwana, Charlie;Ollikainen, Noah
背景：糖皮质激素受体（GR）和盐皮质激素受体（MR）是由共同的祖先进化而来的。仍然没有完全理解的是糖皮质激素的特异性（e。G.皮质醇）和盐皮质激素（e. G.醛固酮）在这些受体中进化。我们在人GR和MR的3D结构的背景下对几种脊椎动物GR和MR的分析表明，除了冰鞋GR（一种软骨鱼）之外，在所有GR中，在对应于人MR中Ser-949的位置处存在缺失。该缺失发生在螺旋12之前的环中，其包含激活功能2（AF 2）结构域，其结合辅激活蛋白并影响类固醇的转录活性。出乎意料的是，我们发现人类MR中的His-950在黑猩猩、猩猩和猕猴的MR中是保守的，在所有硬骨鱼和陆地脊椎动物MR中是谷氨酰胺，包括新世界猴和原猴。GR和MR对皮质类固醇的反应差异的演变涉及GR中对应于人MR中Ser-949的残基的缺失。950在人类MR中可能在与旧大陆猴从原猴出现相关的生理变化中起重要作用。
Background: The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) evolved from a common ancestor. Still not completely understood is how specificity for glucocorticoids ( e. g. cortisol) and mineralocorticoids ( e. g. aldosterone) evolved in these receptors.Results: Our analysis of several vertebrate GRs and MRs in the context of 3D structures of human GR and MR indicates that with the exception of skate GR, a cartilaginous fish, there is a deletion in all GRs, at the position corresponding to Ser-949 in human MR. This deletion occurs in a loop before helix 12, which contains the activation function 2 (AF2) domain, which binds coactivator proteins and influences transcriptional activity of steroids. Unexpectedly, we find that His-950 in human MR, which is conserved in the MR in chimpanzee, orangutan and macaque, is glutamine in all teleost and land vertebrate MRs, including New World monkeys and prosimians.Conclusion: Evolution of differences in the responses of the GR and MR to corticosteroids involved deletion in the GR of a residue corresponding to Ser-949 in human MR. A mutation corresponding to His-950 in human MR may have been important in physiological changes associated with emergence of Old World monkeys from prosimians.