Homodimers, retinoid receptors

The multipUcity of possible combinations of homodimers and heterodimers of RAR and RXR subtypes, and the various possible RXR heterodimers with other receptors, permits a wide variety of active retinoid receptor complexes that bind to different response elements on DNA. Unlike most hormone response elements on DNA, which are palindromic and bind a symmetrical receptor homodimer, the most common type of retinoid response element is a direct repeat purine-G-(G or T)-T-C-A-(Xn)-purine-G-(G or T)-T-C-A, in which the spacer (Xn) is commonly 5 base pairs, but may be 1 or 2. There are also more complex retinoid response elements, including palindromic and inverted palindromic repeats, as well as hexameric motifs with variable spacing. This means that a wide variety of different genes may be regulated differendy in response to retinoids. 

These retinoid receptors must form dimers before they interact with RAREs. RARs must form heterodimers with RXR.S, whereas RXRs may also form homodimers. It appears that the RAREs for the homodimers differ from those for the heterodimers. This implies that they may activate different sets of genes. RXRs also form hetcrodimers with thyroid hormone receptors and vitamin O receptois. increasing their affinity for DNA. Several enzymes whose expression depends on RXR have been found. The available experimental data provide convincing evidence that these proteins are, in fact, nuclear receptors belonging to the steroid/thyroid hormone superfamily. They mediate important aspects of vitamin A function. The existence of proteins that specifically bind retinoic acid substantiates the implication of retinoic acid as a physiological form of vitamin A. 

A number of other nuclear receptors have also been shown to bind and be activated by retinoids. For example, testicular receptor 4 (TR4) has recently been suggested to be a retinoid receptor, because the binding of both retinol and RA can induce conformational changes of TR4 leading to the activation of this receptor (Zhou et al. 2011). TR4 can either function as homodimer or heterodimerize with testicular receptor 2 (TR2) to function in spermatogenesis, hpid and hpoprotein regulation, and central nervous system development (Zhou et al. 2011). However, additional experiments are required to reveal the physiological and developmental implications of the activation of TR4 by retinoids, such as RA (Zhou et al. 2011). 

These nuclear receptors have several common structural features (Figure 43-12). All have a centrally located DNA-binding domain (DBD) that allows the receptor to bind with high affinity to a response element. The DBD contains two zinc finger binding motifs (see Figure 39-14) that direct binding either as homodimers, as heterodimers (usually with a retinoid X... 

Among the receptors for the retinoids (RAR and RXR) there are at least three subtypes characterized, known as RARa, p, and y (RXR a,P and y)- The various subtypes differ from each other mainly in their amino acid sequence and are encoded in each case by their own gene. Furthermore, one finds isoforms of some of the receptors created by alternative splicing of the primary transcript. Altogether, the repertoire of the various receptor variants is enormously increased through the existence of the subtypes and by alternatively spliced receptors. Because the individual variants differ in their ability to form hetero- and homodimers as well as in their abUity to activate and bind ligands, this results in a great variety of functionally different receptors. 

Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

The two families of receptors differ from each other considerably, and RARs show greater sequence homology with thyroid hormone receptors than with RXRs. RARs act only as heterodimers with RXRs homodimers of RARs have poor affinity for retinoid response elements on DNA. The liganded CRABP(II) enhances the binding of the RAR-RXR heterodimer to response elements on DNA and amplifies the effect of the receptor dimer (Delva et al., 1999). 

The vitamin D receptor acts mainly as a heterodimer with the retinoid X receptor (RXR Section 2.3.2.1). Binding of calcitriol induces a conformational change in the receptor protein, permitting dimerization with occupied or unoccupied RXR, followed by phosphorylation to activate binding to the vitamin D response element on DNA (DeLuca and Zierold, 1998). Abnormally high concentrations of 9-cis-retinoic acid result in sequestration of RXR as the homodimers, meaning that it is unavailable to form heterodimers with the vitamin D receptor (or other receptors) excessive vitamin A can therefore antagonize the nuclear actions of vitamin D (Haussler et al., 1995 Rohde et al., 1999). 

Nuclear hormone receptors (NRs) are ligand-activated transcription factors that regulate gene expression by interacting with hormone response elements on target genes (see also Chapter 12). This occurs via the formation of monomers, homodimers, or heterodimers generally with the retinoid X receptor (RXR) and interaction with the hormone response element [83,84],... 

RAR-RXR heterodimer or RXR-RXR homodimer), the activated receptors bind with high affinity to the specific DNA retinoic acid response element (RARE) and effect mRNA transcription. Ultimately, the retinoid response is mediated by primary target genes, by interference with othertranscription factors or by control of certain posttranscriptional actions. 

These receptors, as heterodimers (RAR-RXR) or homodimers (RXR-RXR), function as RA-inducible transcriptional regulatory proteins by binding to DNA regions called retinoic acid response elements (RAREs) or retinoid X response elements (RXREs) located within the promoter of target genes. RAREs consist of direct repeats of the consensus half-site sequence AGGTCA separated most... 

The classical sex hormone receptors such as ER, PR, and AR form homodimers upon ligand binding and then interact with target DNA via HREs to control target gene expression (Figure 2.1fi). In contrast, the orphan receptors or adopted orphan receptors form heterodimers with retinoid X receptors (RXRs) on direct repeat... 

Carlberg, C., Hooft van Huijsduijnen, R., Staple, J. K., DeLamarter, J. F., and Becker-Andre, M. (1994) RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol. Endocrinol. 8, 757-770. 

Unlike the steroid receptors, most of which function as homodimers, a second class of NRs function as heterodimers with the retinoid X receptor (RXR). Importantly, these receptors serve as sensors for metabolites such as fatty acids, oxysterols, and bile acids. Key elements of ligand recognition and receptor activation have been elucidated following structure-function analyses of several receptors in this family including the PPARs, liver X receptors (LXRs), and FXR. 

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