Steroid hormone receptor Dimerization

The HREs of the steroid hormone receptors posses a palindromic structure, comparable to the DNA binding elements of procaryotic repressors (see fig. 4.7a). The glucocorticoid receptor, for example, binds as a homodimer to the two-fold symmetrical recognition sequence, whereby the receptor is already dimerized in solution. In complex with the DNA each subimit of the dimer contacts one half-site of the HRE. As a consequence of the two-fold repeat of the recognition sequence, a high affinity binding of the receptor dimer results (compare 1.2.4). 

Fig. 4.8. Functional domains, DNA-binding and HRE structure of the steroid hormone receptors. a) domain structure of the steroid hormone receptor. AFl, AF2 domains that mediate the stimulation of the transcription, b) schematic representation of the two Zn -Cys4 binding motils of the DNA-binding domains, c) Complex formation between the dimeric DNA-binding domains of the gluccocorticoid receptor and the HRE. The black spheres represent Zn ions. After Luisi et al., 199L d) Consensus sequence and configuration of the HRE elements of the steroid hormone receptor.

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. 

Figure 17.4 Intracellular steroid receptor activation by hormone ligands, (a) Steroid hormones diffuse across the cell membrane into the cell. (b) Steroid hormone receptors in the basal state bound to accessory proteins, (c) Steroid hormones bind to receptors and accessory proteins are dissociated from the receptors. (d) Hormone receptor complexes dimerize. (e) Dimer complexes enter the nucleus and initiate transcription of responsive genes.

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

Fig. 16.13. Steroid hormone receptors. A. Domains of the steroid hormone receptor. The transactivation domain (TAD) binds coactivators DNA-binding domain (DBD) binds to hormone response element in DNA ligand-binding domain (LBD) binds hormone NLS is the nuclear localization signal the dimerization sites are the portions of the protein involved in forming a dimer. The inhibitor binding site binds heat shock proteins and masks the nuclear localization signal. B. Transcriptional regulation by steroid hormone receptors. Additional abbreviations HSP, heat shock proteins GRE, glucocorticoid response element GIZ, glucocorticoid receptor.

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

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