Abstract
ABSTRACTMutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone α (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function unexpectedly retain the ability to bind thyroid hormone. Visualization of the ligand T3 within the crystal structure of a prototypic TRα mutant validates this notion. This finding prompted the synthesis of different thyroid hormone analogues, identifying a lead compound, ES08, which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex for treatment of RTHα.
Highlights
The physiological effects of thyroid hormones (TH: thyroxine, T4; triiodothyronine T3), are mediated by its canonical action via nuclear thyroid hormone receptors (TR, TR ), with differing tissue distribution, which regulate transcription of target genes in a ligand-dependent manner[1]
Resistance to Thyroid Hormone α (RTH) due to heterozygous TR mutations, manifests with features of hypothyroidism reflecting hormone resistance in TR -expressing tissues, but associated paradoxically with near-normal circulating TH levels. 19 different THRA defects have been recorded in different families worldwide, with a significant subset (8/19) being frameshift or premature stop mutations which disrupt the receptor carboxyterminus and are associated with a severe phenotype[8]
To determine whether these mutations mediate failure of corepressor displacement or coactivator recruitment or a combination, we used a fluorescence anisotropy assay to investigate the ability of wild-type and mutant TRα ligand-binding domains (LBDs) to bind to peptide motifs derived from corepressor and coactivator receptor interaction domains, in the presence and absence of T3
Summary
The physiological effects of thyroid hormones (TH: thyroxine, T4; triiodothyronine T3), are mediated by its canonical action via nuclear thyroid hormone receptors (TR , TR ), with differing tissue distribution, which regulate transcription of target genes in a ligand-dependent manner[1]. TRs recruit a multiprotein complex, containing corepressor (CoR, e.g. nuclear receptor corepressor, NCoR; silencing mediator of retinoic acid and thyroid hormone receptor, SMRT) and histone deacetylase (HDAC), to inhibit target gene transcription. Receptor occupancy by ligand (T3) promotes dissociation of this corepressor complex with relief of transcriptional repression, and mediates recruitment of a protein complex containing coactivators RTH due to heterozygous TR mutations, manifests with features of hypothyroidism (skeletal dysplasia and growth retardation, neurocognitive impairment, low metabolic rate, reduced intestinal transit) reflecting hormone resistance in TR -expressing tissues, but associated paradoxically with near-normal circulating TH levels. 19 different THRA defects have been recorded in different families worldwide, with a significant subset (8/19) being frameshift or premature stop mutations which disrupt the receptor carboxyterminus and are associated with a severe phenotype[8]
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