Understanding the molecular mechanism of dominant negative action of mutant thyroid hormone beta 1-receptors: the important role of the wild-type/mutant receptor heterodimer.

• DOI: 10.1210/endo.137.2.8593822
• Publication Date: 2014-01-08T16:07:41Z
• Authors: X G Zhu; C L Yu; P McPhie; R Wong; S Y Cheng
• Keywords: BETA (programming language); Thyroid hormone receptor; Mechanism of Action

The clinical manifestations of patients with resistance to thyroid hormone result from inhibition the functions wild-type receptors (wTRs) by dominant negative effect mutant TR beta 1 (mTR 1). One proposed mechanisms which mTR exerts its action is via formation putative inactive wTR 1/mTR heterodimer. However, nature heterodimer poorly understood. present study characterizes electrophoretic mobility shift assay. used was PV, contains a frame mutation in C-terminal part and has less than 1% T3 binding affinity 1. Because difficulty resolving PV dimers, we truncated A/B domain deleted (delta 1) demonstrate on response elements (TREs) half-site motifs are oriented an inverted repeat (F2), direct separated four nucleotides (DR4), or (Pal). Deletion had no TREs In presence equal amounts delta three types molecular complexes. homodimer, 1/PV heterodimer, homodimer bound each TRE ratio approximately 1:2:1. identities these complexes were confirmed their ability be supershifted anti-TR and/or anti-PV antibodies. varied different TREs. apparent constant (Ka) F2:DR4:Pal = 6:2:1. dependent. No T3-induced dissociation observed for when F2 Pal. contrast, DR4 dissociated ED50 3.9 +/- 0.9 nM. F2, DR4, Pal values 4.1 1.2, 1.3 0.3, more 100 nM, respectively. By transfection assays, found dependent rank order >> > ME (a DR4-like rat malic enzyme gene). Taken together, results indicate strong correlation between potency PV. These suggest that could play important role