Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation
Antihormones are potent antagonists of hormone action in vivo, but the mechanism underlying this antagonism is not understood. Several steroid hormones transform (activate) their receptors from a cytosolic, non-DNA binding 8 S sedimentation form to a nuclear, DNA binding 4 S form. Transformation is...
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Published in | The Journal of biological chemistry Vol. 267; no. 27; pp. 19513 - 19520 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Biochemistry and Molecular Biology
25.09.1992
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Subjects | |
Online Access | Get full text |
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Summary: | Antihormones are potent antagonists of hormone action in vivo, but the mechanism underlying this antagonism is not understood.
Several steroid hormones transform (activate) their receptors from a cytosolic, non-DNA binding 8 S sedimentation form to
a nuclear, DNA binding 4 S form. Transformation is accompanied by the loss of associated heat shock proteins. We have previously
demonstrated that an additional hormone-dependent step, separate from heat shock protein removal, is required for activation
of the human progesterone receptor. We have devised an assay in which the human progesterone receptor translated in vitro
binds to its specific response element in a hormone-dependent manner. As assessed by limited proteolytic digestion, hormone
treatment of the nascent receptor induces a dramatic conformational change within the protein. The conformational change occurs
in the absence of DNA and renders the entire ligand binding domain resistant to digestion by proteases. A number of antiprogestins,
including RU486, induce an equally dramatic, but distinct, structural alteration of the ligand binding domain. The distinction
centers upon the final 30 to 40 amino acids at the carboxyl terminus. The conformational change can be induced by ligand prior
to dissociation of the 8 S complex and is not induced by heat shock protein removal in the absence of hormone. Remarkably,
virtually identical hormone-induced conformational changes were detected following proteolytic analysis of in vitro translated
retinoic acid receptors. Our data indicate that the sole necessary event in the activation of steroid receptors is conformational
modification by the ligand. Furthermore, we conclude that transcriptional inactivation of steroid receptors by antihormones
involves the induction of an inappropriate structural conformation at the extreme carboxyl terminus of the ligand binding
domain. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1016/s0021-9258(18)41805-4 |