Abstract
AbstractThe origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ER[alpha] are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ER[alpha] in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors.
Highlights
Estradiol has diverse physiological actions in vertebrates [1,2,3], many of which are mediated by binding to the estrogen receptor [ER], a member of the nuclear receptor family, which is a large and diverse family of transcription factors [4,5,6,7,8]
Phylogenetic analysis of vertebrate steroid receptors shows that the ER is separate from the androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) [4, 6, 7, 9], which correlates with their steroid specificity
Our 3D model of amphioxus SR predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors
Summary
Estradiol has diverse physiological actions in vertebrates [1,2,3], many of which are mediated by binding to the estrogen receptor [ER], a member of the nuclear receptor family, which is a large and diverse family of transcription factors [4,5,6,7,8]. Some key interactions between estradiol and human ERα are conserved in amphioxus SR, which can explain the activation of SR by E2 and the lack of response to 3-ketosteroids.
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