Thyroid hormone receptor binding

As summarized in Figure 52-3, steroid/thyroid hormone receptors bind to other proteins as well as to DNA [7-9]. 

Figure 7.4 The effect of bile acids on energy expenditure. Circulating bile acids bind to the G-protein-coupled receptor, TGR5 that stimulates increased cAMP-PKA activation and increased expression of type-2 iodothyronine deiodinase (D2). This response is sensitised by a high-fat diet. D2 converts thyroxine (T4) to active 3,5,3 -tri-iodothyronine (T3). T3 stimulates thyroid hormone receptor binding to target genes. This leads to altered expression of genes associated with energy balance, and increased energy expenditure.

Thyroid hormone receptors bind their sites on the promoter regions of DNA in the absence of bonnd hormone, usually resulting in transcriptional repression. 

Most of the intracellular receptors reside principally in the nucleus, and some of these are constitutively bound, as dimers, to their response element in DNA (e.g., the thyroid hormone receptor). Binding of the hormone changes its activity and its ability to associate with, or disassociate from, DNA. Regulation of gene transcription by these receptors is described in Chapter 16. 

Ko L, Cardona GR, Chin WW. Thyroid hormone receptor-binding protein, an UOCLL motif-containing protein, functions as a general coactivator. Proc Natl Acad Sci USA 2000 97(11) 6212-6217. 

Spindler, B. J, MacLeod, K. M., Ring, J., and Baxter, J. D. (1975). Thyroid hormone receptors binding characteristics and lack of hormonal dependenct for nuclear localization. J. Biol. Chem. 250 4113-4119. 

Van Beeren HC, Jong WMC, Kaptein E et al (2003) Dronedarone acts as a selective inhibitor of 3,5,3 -triiodothyronine binding to thyroid hormone receptor-a. in vitro and in vivo evidence. Endocrinology 144 552-558... 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

Thyroid Hormone Receptor (TR) can bind to the LTR in vivo independently of its ligand and regulates promoter activity. ChIP assays with anti-acetylated-histone antibodies revealed that unliganded TR reduce the local histone acetylation levels at the HIV-1 LTR, while thyroid hormone treatment reverses this induction (Hsia and Shi, 2002). Accordingly, unliganded TR recruits co repressors and at least one HDAC (Hsia and Shi, 2002). 

Cellular Uptake and Intracellular Binding of T3 to Nuclear Thyroid Hormone Receptors... 

A) Thiocyanate inhibits the binding of iodide to thyroid hormone receptors. 

Miyamoto, T, Kaneko, A., Kakizawa, T, Yajima, H., Kamijo, K., Sekine, R., Hiramatsu, K., Nishii, Y, Hashimoto, T. Hashizume, K. (1997) Inhibition of peroxisome proliferator signaling pathways by thyroid hormone receptor. Competitive binding to the response element. J. biol. Chem., Ill, 7752-7758... 

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