Abstract
Molecular dynamics simulations were used to determine the binding affinities between the hormone 17-estradiol (E2) and different estrogen receptor (ER) isoforms in the rainbow trout, Oncorhynchus mykiss. Previous phylogenetic analysis indicates that a whole genome duplication prior to the divergence of ray-finned fish led to two distinct ER isoforms, ER and ER, and the recent whole genome duplication in the ancestral salmonid created two ER isoforms, ER and ER. The objective of our computational studies is to provide insight into the underlying evolutionary pressures on these isoforms. For the ER subtype our results show that E2 binds preferentially to ER over ER. Tests of lineage specific N/S ratios indicate that the ligand binding domain of the ER gene is evolving under relaxed selection relative to all other ER genes. Comparison with the highly conserved DNA binding domain suggests that ER may be undergoing neofunctionalization possibly by binding to another ligand. By contrast, both ER and ER bind similarly to E2 and the best fitting model of selection indicates that the ligand binding domain of all ER genes are evolving under the same level of purifying selection, comparable to ER.
Highlights
Estrogens are essential endogenous hormones that modulate the development and homeostasis of a wide range of target tissues, such as the reproductive tracts, breast and skeletal system [1]
The ERa isoforms, on the other hand, appear to have arisen as a result of a second more recent whole genome duplication event that occurred in the salmonid ancestor 25–100 million years ago [10]. These results indicate that the second ERa isozyme that arose during the earlier genome duplication appears to have been lost subsequently, since no other ray finned fish are known to have a second ERa isoform
Our results show that E2 binds preferentially to ERa1 over ERa2
Summary
Estrogens are essential endogenous hormones that modulate the development and homeostasis of a wide range of target tissues, such as the reproductive tracts, breast and skeletal system [1]. Estrogenic hormones have multi-faceted and wide-ranging effects in vertebrate animals. For estrogens such as 17b-estradiol (E2) to exert their biological effects, they must interact with cellular estrogen receptors (ER). The other pathway provides direct genomic control in which ERs act as transcription factors within the cell nucleus [4,5]. These ERs are members of the nuclear receptor superfamily of ligand-modulated transcription factors [6,7,8]. There are two different subtypes of these ERs, referred to as a and b, each encoded by a separate gene
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