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Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2022 Feb; Vol. 298 (2), pp. 101574. Date of Electronic Publication: 2022 Jan 08. - Publication Year :
- 2022
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Abstract
- The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR <superscript>dim/dim</superscript> mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GR <superscript>D/D</superscript> ) have previously helped to define the functions of GR monomers and dimers. Since GR <superscript>D/D</superscript> retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GR <superscript>D+L/D+L</superscript> mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GR <superscript>L/L</superscript> 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 <subscript>d</subscript> 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.<br />Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article.<br /> (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 298
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35007536
- Full Text :
- https://doi.org/10.1016/j.jbc.2022.101574