Short tandem repeats in the inhibitory domain of the mineralocorticoid receptor: prediction of a ?-solenoid structure.

ABSTRACT: BACKGROUND: The human mineralocorticoid receptor (MR) is one of the main components of the renin-angiotensin-aldosterone system (RAAS), the system that regulates the body exchange of water and sodium. The evolutionary origins of this protein predate those of renin and the RAAS; accordingly it has other roles, which are being characterized. The MR has two trans-activating ligand independent domains and one inhibitory domain (ID), which modulates the activity of the former. The structure of the ID is currently unknown. RESULTS: Here we report that the ID contains at least 15 tandem repeats of around 10 amino acids, which we computationally characterize in the human MR and in selected orthologs. This ensemble of repeats seems to have emerged around 450 million years ago, after the divergence of the MR from its close homolog, the glucocorticoid receptor, which does not possess the repeats. The region would have quickly expanded by successive duplication of the repeats stabilizing at its length in human MR shortly after divergence of tetrapoda from bony fishes 400 million years ago. Structural predictions, in combination with molecular dynamics simulations suggest that the repeat ensemble forms a ?-solenoid, namely a ?-helical fold with a polar core, stabilized by hydrogen-bonded ladders of polar residues. Our 3D-model, in conjunction with previous experimental data, implies a role of the ?-helical fold as a scaffold for multiple intra-and inter-molecular interactions and that these interactions are modulated via phosphorylation-dependent conformational changes. CONCLUSIONS: We, thus, propose that the structure of the repeat ensemble plays an important role in the coordination and sequential interactions of various MR partners and therefore in the functionality and specificity of MR.

SUBMITTER: Vlassi M 

PROVIDER: S-EPMC3851330 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature