Part of “CHAPTER 31 – THYROID PHYSIOLOGY: HORMONE ACTION, RECEPTORS, AND POSTRECEPTOR EVENTS“

Two related TRs, which have been identified, bind TH with high affinity and specificity6,7; these TRs, initially called c-erbAs, are protooncogenes of a previously described viral oncogene product, v-erbA, that causes erythroblastosis in chicks. On the basis of amino-acid sequence homology and similarity in the organization of functional domains of receptors, TRs belong to a large superfamily of nuclear-hormone receptors that include the steroid hormone, vitamin D, and retinoic acid receptors.

Like the other family members, TRs contain a central DNA-binding domain with two “zinc finger” motifs and a carboxy-terminal ligand-binding domain8,9 (Fig. 31-2). The ligand-binding domain is important for ligand binding and also for transactivation and dimerization. X-ray crystallographic studies of liganded
TR have shown that TH is embedded in a hydrophobic pocket flanked by discontinuous stretches of the ligand-binding domain.10 A subregion important for transcriptional activation (AF-2)11,12 also exists at the extreme carboxy terminus. This subregion is highly conserved within the nuclear-hormone receptor superfamily and appears to undergo a major conformational change on ligand binding.11,12 The ligand-binding domain contains at least nine hydrophobic, heptad repeats, which potentially may be involved in TR homo- and heterodimerization.13 Mutations in the ninth heptad region abrogates TR heterodimerization, thus suggesting that this may be a particularly important region for dimerization. The hinge region between the DNA- and TH-binding domains contains a nuclear-localization motif common among nuclear-hormone receptors.8,9 However, unlike steroid-hormone receptors, which associate with cytoplasmic heat shock proteins in the absence of ligand, TRs are localized predominantly in the nucleus and bind DNA even in the absence of ligand.