The hormone binding domain

Our present information about the hormone binding domain, although still limited, comes from a combination of biochemical and genetic studies. The amino acid which reacts with the chemical affinity label dexamethasone 21-mesylate has now been identified as cysteine in position 656 of the rat glucocorticoid receptor [109]. This cysteine is therefore located within or very close to the hormone binding site. It corresponds to cysteine 644 of the mouse receptor (Fig. 2). 

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Hurley DM, Accili D, Stratakis CA, et al. (1991) Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in famUial glucocorticoid resistance. J Clin Invest. 87, 680-686. 

The receptors for lipophilic signaling substances all belong to one protein superfamily. They are constructed in a modular fashion from domains with various lengths and functions. Starting from the N terminal, these are the regulatory domain, the DNA-binding domain, a nuclear localization sequence (see p. 228), and the hormone-binding domain (see p. 73D). 

Activation of steroid hormone receptors by the hormone. In the absence of the hormone, the steroid receptors are complexed through the hormone-binding domain to another protein known as heat shock protein 90 (hsp90). Both the hormone-binding domain and the hsp90 prevent functional interaction of the receptor with DNA. Binding of the hormone frees the receptor from hsp90 and promotes dimerization of the receptor, which can then bind to the palindromic hormone response element (HRE) and activate transcription. 

Another protein hormone, epidermal growth factor, is bound to the extracellular domain of its receptor. A mutated form of the receptor, which lacks the hormone-binding domain, results in the kinase activity being permanently on. This leads to cancer because the cell is signaled to grow at all times—the hallmark of cancer. 

As an extension to the deletion studies decribed above several double mutations have been constructed which, upon transfection, produced receptor derivatives truncated at both ends of the polypeptide chain [82,83,90]. These are missing both the M domain and the hormone binding domain or parts thereof but are still able to bind DNA. A receptor fragment of only 150 amino acids was sufficient for constitutive transcriptional activation. This suggests that the DNA binding domain of... 

J. A., Luthey-Schulten, Z. A., Seielstad, D. A., Wolynes, P. G. Three-Dimensional Model for the Hormone Binding Domains of Steroid Receptors, Proc. Natl. Acad. Sci. USA 1993,90, 9949-9953. 

Lemesle-Varloot, L., Ojasoo, T, Momon, J. P., Raynaud, J. P. A Model for the Determination of the 3D-Spatial Distribution of the Functions of the Hormone- Binding Domain of Receptor that Bind 3-keto-4-ene Steroids,... 

Modarress KJ, Opoku J, Xu M, Sarlis NJ, Simons SS Jr. Steroid-induced conformational changes at ends of the hormone binding domain in the rat glucocorticoid receptor are... 

Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR. 1996. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc. Natl. Acad. Sci. USA 93 4948-52... 

Tagawa, M., H. Hagiwara, A. Takemura, S. Hirose and T. Hirano. Partial cloning of the hormone-binding domain of the cortisol receptor in tilapia, Oreochromis mossambicus, and changes in the mRNA level during embryonic development. Gen. Comp. Endocrinol. 108 132-140, 1997. 

Cre function can also be regulated on a post-transcriptional level. If the cre recom-binase is fused with a mutated hormone binding domain of a steroid receptor, the fusion protein is sequestered into the cytosol and cannot reach the nucleus [20]. Only in the presence of a specific steroid binding to the hormone binding domain can the fusion protein translocate to the nucleus, where it will catalyze the DNA deletion. 

A EXPERIMENTAL FIGURE 11-43 Fusion proteins from expression vectors demonstrate that the hormone-binding domain of the glucocorticoid receptor (GR) mediates translocation to the nucleus in the presence of hormone. Cultured animal cells were transfected with expression vectors encoding the proteins diagrammed at the bottom. Immunofluorescence with a labeled antibody specific for p-galactosidase was used to detect the expressed proteins in transfected cells, (a) In cells that expressed p-galactosidase alone, the enzyme... 

Ekena, K., K. E. Weis, J. A. KatzeneUenbogen, andB. S. Katzenellenbogen. 1996. Identification of amino acids in the hormone binding domain of human estrogen receptor important in estrogen binding. Journal of Biological Chemistry 27 20053-20059. 

Munoz, A., Zenke, M., Gehring, U., Sap, J., Beug, H., and Vennstrom, B. (1988), Characterization of the hormone-binding domain of the chicken/thyroid hormone receptor protein. EMBO J. 7 155-159. 

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