Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β

The Journal of Clinical Endocrinology and Metabolism
Karn WejaphikulW Edward Visser

Abstract

The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity. Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4. Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed. Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited...Continue Reading

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Citations

Sep 19, 2019·Thyroid : Official Journal of the American Thyroid Association·Karn WejaphikulMarcel E Meima
Jun 3, 2021·Cancers·Gabriella SchieraItalia Di Liegro
Jul 24, 2021·Trends in Endocrinology and Metabolism : TEM·Valentina CapelliMiguel López
Sep 4, 2021·Endocrine Reviews·Peter R EbelingFrances Milat

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Methods Mentioned

BETA
exome sequencing
transfection
two-hybrid

Key Resources (RRID) Mentioned

CVCL_0363

Software Mentioned

PovRay
YASARA Structure
GraphPad Prism

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