Small, hydrophobic signaling molecules such as steroid hormones are able to diffuse through the plasma membrane of the target cell and to bind intracellular receptors in the nucleus or cytoplasm. These receptors, often called nuclear hormone receptors, are therefore inducible transcription factors. Following ligand binding, the receptor protein is activated and associates with a specific DNA response element located in the promoter regions of perhaps 50–100 target genes and, with the help of suitable co-activator proteins, activates their transcription.
The receptors for steroid hormones, and also those for the signaling molecules thyroxine and retinoic acid, belong to a common nuclear receptor superfamily. Each receptor in this superfamily contains a centrally located DNA-binding domain of about 68 amino acids, and a ligand-binding domain of about 240 amino acids located close to the C-terminus (Figure 1A). The DNA-binding domain contains structural motifs known as zinc fingers and binds as a dimer, with each monomer recognizing one of two hexanucleotides in the response element. The two hexanucleotides are either inverted repeats or direct repeats, typically separated by three or five nucleotides (Figure 1B).
Fig1. The nuclear receptor superfamily. (A) Members of the nuclear receptor superfamily all have a similar structure, with a central DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD). Numbers refer to the protein size in amino acid residues. GR, glucocorticoid receptor; ER, estrogen receptor; RAR, retinoic acid receptor; TR, thyroxine receptor; VDR, vitamin D receptor. (B) The response elements recognized by the nuclear receptors also have a conserved structure, with two hexanucleotide recognition sequences typically separated by either three or five nucleotides (n). The hexanucleotide sequences have the general consensus of AGNNCA with the two central nucleotides (pale orange shading) conferring specificity and belonging to one of three classes: AA, AC, or GT.
The nuclear hormone receptors are normally found in the cytoplasm. They are transcription factors that in the absence of bound ligand are maintained in an inactive state: either the ligand-binding domain directly represses the DNA-binding domain, or the receptor is bound to an inhibitory protein (as in the case of the glucocorticoid receptor; see Figure2). Binding of the ligand to the receptor overcomes the inhibition and the activated ligand–receptor complex migrates to the nucleus, where it works as a specific transcription factor.
Fig2. Cell signaling by ligand activation of an intracellular receptor. A glucocorticoid (GC), like other hydrophobic hormones, can pass through the plasma membrane and bind to a specific intracellular receptor. The glucocorticoid receptor (GR) is normally bound to an Hsp90 inhibitory protein complex and is found within the cytoplasm. After binding of the receptor to glucocorticoid, however, the inhibitory complex is released and the now-activated receptor forms dimers and translocates to the nucleus. Here, it works as a transcription factor by specifically binding to a particular response element sequence in target genes (shown in the lower panel; see also Figure 1B) and by activating the target genes with the co-operation of specific co-activator proteins.
