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Read about nuclear receptors' mechanism of signaling and structure.
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1. Introduction to nuclear receptors and sub-classification of the super family
Nuclear receptors play many important roles in eukaryotic development, differentiation, reproduction and metabolic homeostasis (Ribeiro et al.,1995; Bain et al., 2006). Proteins of the nuclear receptor super-family are single polypeptide chains with three major domains: a variable amino-terminal domain, a highly conserved DNA-binding domain (DBD), and a less conserved carboxyl-terminal ligand binding domain (LBD). The superfamily is sub-divided into three classes. Class 1 is the steroid receptor family, and includes the progesterone receptor (PR), the estrogen receptor (ER) (Figure 1), the glucocorticoid receptor (GR), the androgen receptor (AR) and the mineralocorticoid receptor. Class 2, or the thyroid/ retinoid family, includes the thyroid receptor (TR), vitamin D receptor (VDR), the retinoic acid receptor (RAR) and the peroxisome proliferator-activated receptor (PPAR). The third class of nuclear receptors is known as the orphan receptor family. This class of nuclear receptor comprises a set of proteins sharing significant sequence homology to known nuclear receptors, but for which the ligands have not yet been identified. Orphan nuclear receptor offer a unique system for the discovery of novel signaling pathways that could provide new drug targets for the treatment of a variety of human diseases.
Figure 1: Western blot of the estrogen receptor
Expression of exogenous estrogen receptor (ER) in HEK293a cells.
2. Nuclear receptors and mechanisms of signaling
All nuclear receptors modulate gene transcription, although amongst the three classes there are differences in the mechanisms through which this is achieved (Ribeiro, 1995; Aranda and Pascual, 2001; Bain et al., 2006). Ligands for nuclear receptors circulate in the body bound to plasma proteins. Following dissociation from these proteins the ligands enter cells and bind to their receptors. Steroids and vitamin D probably enter cells through passive diffusion, whereas thyroid hormone and retinoic acid might gain cellular entrance via specific transport processes.
Steroid receptors are bound to Hsps, such as Hsp90 and Hsp70, in the cytoplasm. Upon binding ligand, the free receptors then translocate to the nucleus and bind as homodimers to imperfect palindromic response elements at upstream promoter sites. DNA binding is coupled to the recruitment of transcriptional co-activators such as the p160 family (Xu and Li, 2003). Nuclear receptors can in some instances repress gene expression in a ligand-dependent manner, and in some cases promote gene transcription.
The class 2 nuclear receptors typically function as heterodimers. TR, VDR, RAR and PPAR associate with the retinoid X receptor (RXR) and bind as a dimeric complex to direct repeat response elements (Ribeiro, 1995; Aranda and Pascual, 2001; Eckey et al., 2003; Bain et al., 2006). The heterodimers are bound to their response element regardless of whether ligands are present and in the absence of heat shock proteins. Gene activation is suppressed by co-repressors such as silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) and nuclear co-repressor (NCoR). Co-repressors are displaced by ligand binding allowing transcriptional activation to take place (Collingwood et al., 1999).
3. Nuclear receptor structure
A typical nuclear receptor consists of a variable NH2 terminal region (the A/B domain) and a highly conserved DNA-binding domain (DBD or C domain) (Tata, 2002; Robinson-Rechavi et al., 2003; Bain et al., 2006). The DBD contains a P-box, which is a short motif responsible for DNA-binding specificity and is involved in dimerization of nuclear receptors including the formation of both heterodimers and homodimers. The elucidiation of the 3D structure of the DBD reveals the presence of two zinc fingers.
A linker region known as domain D is situated between the DBD and the ligand binding domain. This region functions as a flexible hinge and contains the nuclear localization signal. Phosphorylation of the hinge region is coupled with increased transcriptional activation. The ligand binding domain (LBD or E domain) is responsible for the binding of cognate ligand or hormone. This domain also contains a ligand-regulated transcriptional activation function (AF-2) necessary for recruiting transcriptional co-activators, which interact with chromatin remodeling proteins and the general transcriptional activation machinery. Most nuclear receptors contain an amino acid sequence N-terminal to the DBD in the variable A/B domain, which contains a transcriptional activation function known as AF-1. In contrast to the moderately conserved AF-2, the AF-1 shows weak conservation across the nuclear receptor super-family and may mediate differential promoter regulation in vivo. The AF-1 sequence functions as a ligand-independent transcriptional activator, but can also functionally synergize with AF-2. In addition to the domains described above some receptors contain a carboxyl-terminal region (F domain) of unknown function.
Figure 2: Nuclear receptor structure
Proteins of the nuclear receptor super-family are single polypeptide chains consisting of three major domains: a variable amino-terminal domain, a highly conserved DNA-binding domain (DBD), and a less conserved carboxyl-terminal ligand binding domain (LBD). AF: activation function (domain 1 and 2). H: hinge. Mutations in the nuclear hormone receptors lead to a variety of inherited disorders. Mutations in X-linked ARs result in testicular feminization syndrome with androgen unresponsiveness or hypo-responsiveness. Glucorticoid resistance and hereditary vitamin D resistant rickets are rare autosomal recessive disorders linked to mutations in the LBD or the DBD of the GR or the VDR respectively (Ribeiro et al., 1995).