Dimerization of the Mineralocorticoid Receptor Ligand Binding Domain by
helix 9, 10 and the F-domain
Abstract
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 (LBD)
domains, with the latter thought to provide the largest dimerization
interface. However, at the structural level, the LBD dimerization of
oxo-steroidian receptors has remained largely a matter of debate. This
is linked to the receptor refractory expression, purification and
crystallization. As a result, there is currently no consensus on a
common homodimer assembly across the 4 receptors, i.e. GR, PR, AR and
MR, despite their sequence homology. Examining the available MR LBD
crystals and using widely plebiscited tools such as PISA, PRISM and
EPPIC, and the MM/PBSA method, we have determined that an interface
mediated by the helices H9 and H10 of the LBD as well as by the F domain
presents the features of a biological protein-protein interaction
surface. This interface which has been observed in both GR alpha and MR
crystals, distinguished itself among other contacts and provided for the
first time a homodimer architecture that is common to both
oxo-steroidian receptors.