Restored mutant receptor:Corticoid binding in chaperone complexes by trimethylamine N-oxide

Without a glucocorticoid (GC) ligand, the transcription factor glucocorticoid receptor (GR) is largely cytoplasmic, with its GC-binding domain held in high affinity conformation by a cluster of chaperones. Binding a GC causes serial dis- and re-associations with chaperones, translocation of the GR t...

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Bibliographic Details
Published in:PloS one 2017-03, Vol.12 (3), p.e0174183-e0174183
Main Authors: Miller, Aaron L, Elam, W Austin, Johnson, Betty H, Khan, Shagufta H, Kumar, Raj, Thompson, E Brad
Format: Article
Language:English
Subjects:
Adrenal Cortex Hormones - metabolism
Animals
Apoptosis
Binding
Binding sites
Biochemistry
Biology and Life Sciences
Cell Line
Chaperones
Chemical properties
Conformation
Deoxyribonucleic acid
DNA
Globular clusters
Glucocorticoids
Humans
Kinases
Methylamines
Methylamines - metabolism
Molecular biology
Molecular chaperones
Molecular Chaperones - metabolism
Physical Sciences
Protein Binding
Proteins
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Research and Analysis Methods
Restoration
Transcription factors
Translocation
Trimethylamine
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Summary:Without a glucocorticoid (GC) ligand, the transcription factor glucocorticoid receptor (GR) is largely cytoplasmic, with its GC-binding domain held in high affinity conformation by a cluster of chaperones. Binding a GC causes serial dis- and re-associations with chaperones, translocation of the GR to the nucleus, where it binds to DNA sites and associates with coregulatory proteins and basic transcription complexes. Herein, we describe the effects of a potent protective osmolyte, trimethylamine N-oxide (TMAO), on a conditions-dependent "activation-labile" mutant GR (GRact/l), which under GR-activating conditions cannot bind GCs in cells or in cell cytosols. In both cells and cytosols, TMAO restores binding to GRact/l by stabilizing it in complex with chaperones. Cells bathed in much lower concentrations of TMAO than those required in vitro show restoration of GC binding, presumably due to intracellular molecular crowding effects.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0174183