Insights into mineralocorticoid receptor homodimerization from a combined molecular modeling and bioinformatics study

In vertebrates, the mineralocorticoid receptor (MR) is a steroid-activated nuclear receptor (NR) that plays essential roles in water-electrolyte balance and blood pressure homeostasis. It belongs to the group of oxo-steroidian NRs, together with the glucocorticoid (GR), progesterone (PR), and androgen (AR) receptors. Classically, these oxo-steroidian NRs homodimerize and bind to specific genomic sequences to activate gene expression. NRs are multi-domain proteins, and dimerization is mediated by both the DNA (DBD) and ligand binding domains (LBDs), with the latter thought to provide the largest dimerization interface. However, at the structural level, the dimerization of oxo-steroidian receptors LBDs has remained largely a matter of debate and, despite their sequence homology, there is currently no consensus on a common homodimer assembly across the four receptors, that is, GR, PR, AR, and MR. Here, we examined all available MR LBD crystals using different computational methods (protein common interface database, proteins, interfaces, structures and assemblies, protein-protein interaction prediction by structural matching, and evolutionary protein-protein interface classifier, and the molecular mechanics Poisson-Boltzmann surface area method). A consensus is reached by all methods and singles out an interface mediated by helices H9, H10 and the C-terminal F domain as having characteristics of a biologically relevant assembly. Interestingly, a similar assembly was previously identified for GR alpha, MR closest homolog. Alternative architectures that were proposed for GR alpha were not observed for MR. These data call for further experimental investigations of oxo-steroid dimer architectures.

Automated summary

The study examined all available MR LBD crystals using different computational methods and identified an interface mediated by helices H9, H10 and the C-terminal F domain as having characteristics of a biologically relevant assembly. Interestingly, a similar assembly was previously identified for GR alpha, the closest homolog of MR, while alternative architectures proposed for GR alpha were not observed for MR. This data suggests the need for further experimental investigations of oxo-steroid dimer architectures.