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bioRxiv · 10.1101/2021.01.20.427507

Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

Lin, X.·Takagi, W. T.·Hyodo, S.·Ijiri, S.·Katsu, Y. K.·Baker, M. E.
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Abstract

We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20{beta}-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. Human PR, in comparison, is activated at 1 nM steroid, only by progesterone and 11-deoxycorticosterone, indicating increased progestin and corticosteroid specificity during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of Cys-528 in elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. Compared to wild-type human PR, there was an increase in activation of human Gly722Cys PR by11-deoxycortisol and a decrease in activation by corticosterone, which may have been important in selection for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.

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Lin, X., Takagi, W. T., Hyodo, S., Ijiri, S., Katsu, Y. K., Baker, M. E.. 2021-01-21. Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective. https://doi.org/10.1101/2021.01.20.427507

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