Open AccessRestored mutant receptor:Corticoid binding in chaperone complexes by trimethylamine N-oxide
Author(s) -
Aaron L. Miller,
W. Austin Elam,
Betty H. Johnson,
Shahjahan Khan,
Raj Kumar,
E. Brad Thompson
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0174183
Subject(s) - trimethylamine n oxide , mutant , chemistry , chaperone (clinical) , receptor , methylamines , microbiology and biotechnology , trimethylamine , biology , biochemistry , medicine , gene , pathology , catalysis
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 (GR act/l ), which under GR-activating conditions cannot bind GCs in cells or in cell cytosols. In both cells and cytosols, TMAO restores binding to GR act/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.