Restored mutant receptor:Corticoid binding in chaperone complexes by trimethylamine N-oxide
Open accessAbstract
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.
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TMAO stabilizes proteins to elevated hydrostatic pressure and impacts protein conformational changes and intracellular molecular crowding.
“TMAO has been shown to stabilize proteins to elevated hydrostatic pressure, and is thought to both impact protein conformational changes, like those that occur with allosteric regulation, and modulate intracellular molecular crowding effects136, 138, 139.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [139]
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References 28 · Cited by 5
- Authors
- Miller, A. L., Elam, W. A., Johnson, B. H., Khan, S. H., Kumar, R., & Thompson, E. B.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Geisinger College of Health Sciences (US)
- Corresponding author
- Thompson, E. Brad
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-03-16
- Volume
- 12
- Issue
- 3
- Pages
- e0174183
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5354453
- OpenAlex
- W2597367890
- Cited by
- 5
- References
- 28
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1
- FWCI
- 0.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (5RO1 CA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- glucocorticoid receptor, trimethylamine N-oxide, chaperone complex, glucocorticoid binding, osmolytes, macromolecular crowding, cytosolic chaperones, nuclear translocation
- MeSH terms
- Adrenal Cortex Hormones, Animals, Cell Line, Humans, Methylamines, Protein Binding, Receptors, Glucocorticoid, Molecular Chaperones
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