Abstract
The steroid hormone receptors regulate important physiological functions such as reproduction, metabolism, immunity, and electrolyte balance. Mutations within steroid receptors result in endocrine disorders and can often drive cancer formation and progression. Despite the conserved three-dimensional structure shared among members of the steroid receptor family and their overlapping DNA binding preference, activation of individual steroid receptors drive unique effects on gene expression. Here, we present the first structure of the human mineralocorticoid receptor DNA binding domain, in complex with a canonical DNA response element. The overall structure is similar to the glucocorticoid receptor DNA binding domain, but small changes in the mode of DNA binding and lever arm conformation may begin to explain the differential effects on gene regulation by the mineralocorticoid and glucocorticoid receptors. In addition, we explore the structural effects of mineralocorticoid receptor DNA binding domain mutations found in type I pseudohypoaldosteronism and multiple types of cancer.
Highlights
Steroid hormones are powerful regulators of homeostatic functions such as cell growth, immunity, reproduction, and metabolism [1]
Crystal structure of the mineralocorticoid receptor (MR) DNA binding domain (DBD) – glucocorticoid response elements (GREs) complex To ensure proper folding and activity, we tested the ability of purified MR DBD and glucocorticoid receptor (GR) DBD to bind to a fluorescently labeled GRE via fluorescence polarization (Figure 1a)
Mutations within MR are the primary cause of type 1 pseudohypoaldosteronism, or PHA1 [38]
Summary
Steroid hormones are powerful regulators of homeostatic functions such as cell growth, immunity, reproduction, and metabolism [1]. Steroid hormones exert their effects by binding to steroid hormone receptors (SRs), which include the estrogen receptors as well as members of the NR3C subfamily (i.e. the mineralocorticoid, glucocorticoid, androgen, and progesterone receptors). The SRs contain a N-terminal transactivation domain of variable length, a DNA binding domain (DBD) containing two Cys zinc fingers, and a flexible hinge connecting the DBD to the ligand binding domain (LBD) [3]. The N-terminal transactivation domain and the hinge are of variable lengths and not well conserved among the NR3C receptors. The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which diverged after a gene duplication of an ancient corticoid receptor, show overlap in hormone preference [4]
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