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Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding

Steven Timmermans (UGent) , Nicolette J.D. Verhoog, Kelly Van Looveren, Sylviane Dewaele (UGent) , Tino Hochepied (UGent) , Melanie Eggermont (UGent) , Barbara Gilbert (UGent) , Anne Boerema-de Munck, Tineke Vanderhaeghen (UGent) , Joke Vanden Berghe (UGent) , et al.
(2022) JOURNAL OF BIOLOGICAL CHEMISTRY. 298(2).
Author
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Abstract
The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR(dim/dim) mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GR(D/D)) have previously helped to define the functions of GR monomers and dimers. Since GR(D/D) retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GR(D+L/D+L) mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GR(L/L) mice (these mice have the I634A mutation but not the A465T mutation), displaying improper lung and skin formation. Using embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation assays, RNAseq, dimerization assays, and ligand-binding assays (and K-d values), we found that the lethal phenotype in these mice is due to insufficient ligand binding. These data suggest there is some correlation between GR dimerization potential and ligand affinity. We conclude that even a mutation as subtle as I634A, at a position not directly involved in ligand interactions sensu stricto, can still influence ligand binding and have a lethal outcome.
Keywords
Cell Biology, Molecular Biology, Biochemistry, DNA-BINDING, DIMERIZATION, INFLAMMATION, MECHANISMS, RESISTANCE

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MLA
Timmermans, Steven, et al. “Point Mutation I634A in the Glucocorticoid Receptor Causes Embryonic Lethality by Reduced Ligand Binding.” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 298, no. 2, 2022, doi:10.1016/j.jbc.2022.101574.
APA
Timmermans, S., Verhoog, N. J. D., Van Looveren, K., Dewaele, S., Hochepied, T., Eggermont, M., … Libert, C. (2022). Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding. JOURNAL OF BIOLOGICAL CHEMISTRY, 298(2). https://doi.org/10.1016/j.jbc.2022.101574
Chicago author-date
Timmermans, Steven, Nicolette J.D. Verhoog, Kelly Van Looveren, Sylviane Dewaele, Tino Hochepied, Melanie Eggermont, Barbara Gilbert, et al. 2022. “Point Mutation I634A in the Glucocorticoid Receptor Causes Embryonic Lethality by Reduced Ligand Binding.” JOURNAL OF BIOLOGICAL CHEMISTRY 298 (2). https://doi.org/10.1016/j.jbc.2022.101574.
Chicago author-date (all authors)
Timmermans, Steven, Nicolette J.D. Verhoog, Kelly Van Looveren, Sylviane Dewaele, Tino Hochepied, Melanie Eggermont, Barbara Gilbert, Anne Boerema-de Munck, Tineke Vanderhaeghen, Joke Vanden Berghe, Natalia Garcia Gonzalez, Jolien Vandewalle, Yehudi Bloch, Mathias Provost, Savvas Savvides, Karolien De Bosscher, Wim Declercq, Robbert J. Rottier, Ann Louw, and Claude Libert. 2022. “Point Mutation I634A in the Glucocorticoid Receptor Causes Embryonic Lethality by Reduced Ligand Binding.” JOURNAL OF BIOLOGICAL CHEMISTRY 298 (2). doi:10.1016/j.jbc.2022.101574.
Vancouver
1.
Timmermans S, Verhoog NJD, Van Looveren K, Dewaele S, Hochepied T, Eggermont M, et al. Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding. JOURNAL OF BIOLOGICAL CHEMISTRY. 2022;298(2).
IEEE
[1]
S. Timmermans et al., “Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding,” JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 298, no. 2, 2022.
@article{8747852,
  abstract     = {{The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR(dim/dim) mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GR(D/D)) have previously helped to define the functions of GR monomers and dimers. Since GR(D/D) retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GR(D+L/D+L) mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GR(L/L) mice (these mice have the I634A mutation but not the A465T mutation), displaying improper lung and skin formation. Using embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation assays, RNAseq, dimerization assays, and ligand-binding assays (and K-d values), we found that the lethal phenotype in these mice is due to insufficient ligand binding. These data suggest there is some correlation between GR dimerization potential and ligand affinity. We conclude that even a mutation as subtle as I634A, at a position not directly involved in ligand interactions sensu stricto, can still influence ligand binding and have a lethal outcome.}},
  articleno    = {{101574}},
  author       = {{Timmermans, Steven and Verhoog, Nicolette J.D. and Van Looveren, Kelly and Dewaele, Sylviane and Hochepied, Tino and Eggermont, Melanie and Gilbert, Barbara and Boerema-de Munck, Anne and Vanderhaeghen, Tineke and Vanden Berghe, Joke and Garcia Gonzalez, Natalia and Vandewalle, Jolien and Bloch, Yehudi and Provost, Mathias and Savvides, Savvas and De Bosscher, Karolien and Declercq, Wim and Rottier, Robbert J. and Louw, Ann and Libert, Claude}},
  issn         = {{0021-9258}},
  journal      = {{JOURNAL OF BIOLOGICAL CHEMISTRY}},
  keywords     = {{Cell Biology,Molecular Biology,Biochemistry,DNA-BINDING,DIMERIZATION,INFLAMMATION,MECHANISMS,RESISTANCE}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{15}},
  title        = {{Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding}},
  url          = {{http://doi.org/10.1016/j.jbc.2022.101574}},
  volume       = {{298}},
  year         = {{2022}},
}
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