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Submitted on October 21, 2003
Accepted on June 1, 2004
INSERM U 478, Faculté de Médecine Xavier Bichat, B. P. 416, 16, rue H. Huchard, 75870 Paris Cedex 18, FRANCE
* To whom correspondence should be addressed. E-mail: zennaro{at}infobiogen.fr.
We have investigated the functional consequences of three naturally occurring amino acid substitutions of the human mineralocorticoid receptor (hMR). These mutations are located in the DNA-binding domain (DBD) and the ligand-binding domain (LBD) and are associated with autosomal dominant or sporadic type I pseudohypoaldosteronism (PHA1). All mutant receptors bound specifically to glucocorticoid responsive elements, but presented modified transcriptional properties. The DBD mutant G633R, which possesses a normal affinity for a glucocorticoid responsive element, displayed altered interaction with and a reduced dissociation rate from DNA. Its intracellular localization in the absence of hormone was predominantly nuclear in comparison with predominant cytoplasmic location of hMR. Hormone-dependent nuclear cluster formation was comparable to wild type hMR. These results and the three-dimensional modeling of the interaction of R633 with DNA suggest that altered interaction dynamics with DNA as well as modified intracellular localization may be responsible for submaximal transcriptional potency of hMR. Two LBD mutations, Q776R and L979P were also investigated. Our data confirm the fundamental role of amino acid Q776 for anchoring the C3 ketone group of steroids in the ligand binding pocket. Analysis of LBD conformation of mutant P979 demonstrates the relevance of hydrophobic interactions in the extreme C-terminal tail of the hMR for the correct ligand-binding competent state of the receptor. Our data underline the importance of studying naturally occurring mutants to identify crucial residues involved in hMR function.
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