Role of the C terminus of the glucocorticoid receptor in hormone binding and agonist/antagonist discrimination.
The glucocorticoid receptor (GR) is a hormone-inducible intracellular modulator of specific gene transcription. Both glucocorticoids and progestins bind to the GR, and some progestins are able to activate the receptor. We have characterized a mutation of the mouse GR that restricts transcriptional activation, but not hormone binding, to glucocorticoids. This mutation, Y77ON, is located 13 amino acids from the C terminus of the mouse GR and helps define a region of the receptor that is important for transcriptional specificity. To further characterize this region of the GR, we have constructed a series of chimeric receptors between the glucocorticoid, progesterone, and androgen receptors. We find that the C-terminal 14 amino acids of the GR can be replaced by the equivalent region of the progesterone or androgen receptors with little alteration in either hormone-binding specificity or transcriptional response to agonists and antagonists. The region is required for hormone binding, however, since C-terminal deletions yield inactive receptors. We conclude that even though mutation of the C-terminal 14 amino acids of the GR can lead to alterations in hormone binding specificity and agonist potential, the differential hormone-binding capacities of the glucocorticoid, progesterone, and androgen receptors are not encoded in this region.
Zhang
S
S
Department of Biochemistry and Molecular Biology, Georgetown University Medical School, Washington, DC 20007, USA.
Liang
X
X
Danielsen
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
D010446:Peptide Fragments; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D011374:Progesterone; D003907:Dexamethasone