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J Biol Chem, Vol. 273, Issue 46, 30175-30182, November 13, 1998

Defective Release of Corepressor by Hinge Mutants of the Thyroid Hormone Receptor Found in Patients with Resistance to Thyroid Hormone

From the Thyroid Unit, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

On positive thyroid hormone response elements (pTREs), thyroid hormone receptor (TR) binding to DNA in the absence of ligand (thyroid hormone, T₃) decreases transcription (silencing). Silencing is due to a family of recently described nuclear corepressor proteins (NCoR and SMRT) which bind to the CoR box in the hinge region of TR. Ligand-dependent activation of TR is associated with displacement of corepressors and recruitment of coactivating proteins. Resistance to thyroid hormone (RTH) is due to mutations in the  isoform of the thyroid hormone receptor (TR-). To date, three RTH mutations reportedly with near-normal T₃ binding (A234T, R243Q, and R243W) have been described in or near the CoR box. To determine the mechanism of RTH caused by these mutants, the interaction of wild type (wt) and mutant TRs with the corepressor, NCoR, and the coactivator, SRC-1, was tested in gel-shift assays. As expected, NCoR bound wt TR in the absence of T₃ and dissociated from TR with increasing T₃ concentration. SRC-1 failed to bind wt TR in the absence of T₃, but bound to TR with increasing avidity as T₃ concentrations rose. At no T₃ concentration did both NCoR and SRC-1 bind to wt TR, indicating that their binding to TR was mutually exclusive. Hinge mutants bound NCoR normally in the absence of T₃; however, dissociation of NCoR and recruitment of SRC-1 was markedly impaired except at very high T₃ concentrations. Importantly, hinge mutant TRs when complexed to DNA bound T₃ poorly despite their near-normal T₃ binding in solution. These binding studies correlated with functional assays showing defective transactivation of pTREs by hinge mutants except at high T₃ concentrations. Thus, we describe a novel mechanism of RTH whereby TR hinge mutants selectively affect T₃ binding when complexed to DNA, and prevent NCoR dissociation from TR. Our data also suggest that solution T₃ binding by RTH mutants may not accurately reflect physiologically relevant T₃ binding by TR when bound to DNA.

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