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J Biol Chem, Vol. 274, Issue 51, 36305-36311, December 17, 1999
From Prince Henry's Institute of Medical Research, Clayton,
Victoria, 3168, Australia
The structural determinants of aldosterone
binding specificity in the mineralocorticoid receptor (MR) have not
been determined. The MR has greatest sequence identity with the better
characterized glucocorticoid receptor (GR), which is reflected in their
overlapping ligand binding specificities. There must be subtle sequence
differences that can account for the MR-specific binding of aldosterone
and the shared binding of cortisol. To characterize ligand binding specificity, chimeras were made between the human MR and GR
ligand-binding domains (LBDs). Three points were chosen as break points
to generate a total of 16 different constructs. These chimeric LBDs
were placed in a human GR expression vector containing the GR
DNA-binding and N-terminal domains and assayed by co-transfection into
CV-1 cells with the mouse mammary tumor virus-luciferase reporter
plasmid. Binding of [3H]aldosterone and
[3H]dexamethasone was also measured. All of the
constructs that are potently activated by aldosterone contain amino
acids 804-874 of the MR. The results of the ligand binding experiments
using [3H]aldosterone were consistent with the
transactivation assay. Cortisol activation of the chimeras was
surprisingly complex. Constructs that are activated by cortisol contain
either amino acids 804-874 and 932-984 of the MR or amino acids
598-668 and 726-777 of the GR. However, all of the chimeras retained
the ability to bind the synthetic glucocorticoid
[3H]dexamethasone, and cortisol was able to displace
[3H]dexamethasone binding, suggesting that the
differential effects of cortisol on transcriptional activation are
caused by an effect that occurs downstream of ligand binding. These
results identify a subregion of the MR LBD that confers specificity of
aldosterone binding, which contrasts with cortisol binding where
differential effects between chimeras appear to be mediated by
interactions distal to ligand binding.
Structural Determinants of Aldosterone Binding Selectivity in the
Mineralocorticoid Receptor*
,
*
This work was supported by a postdoctoral fellowship from
the National Heart Foundation of Australia, by the National Health and
Medical Research Council, and by a generous donation from Eva and Les
Erdi.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Prince Henry's Inst.
of Medical Research, P. O. Box 5152, Clayton, Victoria 3168, Australia. Tel.: 61-3-9594-4380; Fax: 61-3-9594-6125; E-mail: fraser.rogerson@med.monash.edu.au.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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