Retinoid X Receptor Like Proteins Background
Retinoid X receptors (RXR) belongs to the nuclear hormone receptor superfamily which includes steroid hormone, thyroid hormone, vitamin D receptors and nuclear receptors including retinoid X receptors, PPAR, LXR and PXR. It is a unique protein in that it has the ability to form heterodimers with one third of the 48 other nuclear receptors giving it the potential to be involved and to converge a large array of signaling pathways. The retinoid X receptors can be ligand dependent or independent and form three different types of dimers; RXR homodimers, permissive heterodimers, and non-permissive heterodimers.
When retinoid X receptor forms homodimers or permissive heterodimers (with PPAR, LXR, PXR etc.) it is amenable to retinoid X receptor ligand dependent activation. This is due to the fact that the activation domain of the partner receptor is placed in proximity to retinoid X receptor helexis so that when RXR is activated by ligand, conformational changes cause direct stabilization of the activation domain of its partner. When RXR forms non-permissive heterodimers (with RAR, VDR, TR etc.) it is not activated by ligand because binding of the other monomer to RXR allosterically inhibits it and the activation domain of the partner is not located in proximity to ligand activated residues in the retinoid X receptor interface.
An unusual protein-protein interaction property of retinoid X receptor is that it can exist in solution as a tetramer. This is due to its unique dimerization interface that is stable in both a symmetric configuration (giving rise to homodimers) and asymmetric configuration (forming heterodimers). When homodimers are formed, a new dimerization interface is formed that allows homodimer-homodimer association and thus the formation of tetramers. Since these tetramers form with high affinity, RXRs may be sequestered within the cell.
During development, RXR-α and β are ubiquitously expressed with the highest levels of RXR-α present in the liver, heart, intestines, kidney, spleen, placenta, and the epidermis. RXR-γ is expressed in all developing skeletal and cardiac muscles, the anterior pituitary, and the brain. The expression of retinoid X receptors is tissue specific and often overlaps but occasionally retinoid X receptors are uniquely expressed. RXR-α is the primary isoform and supports the activity of all three retinoid X receptors. Furthermore, RXR-α may be important in the expression of RXRγ since the RXRγ gene contains a Retinoid X Response Element.
Studies with mice lacking expression of RXR-α have found that these mice die in utero as a result of hypoplastic myocardium and RXR-α null mutations exhibit growth retardation, webbed digits and defects in the chorioallantoic placenta. Loss of RXR-β and RXR-γ is not as severe since they can be compensated for by RXR-α which may explain why RXRγ-/- mouse mutants are viable and have no muscular defects even in compound mutant combinations.
The receptor dimers of retinoid X receptor and its partner, constituitively bind to specific DNA response elements in the promoters or enhancers of the genes they govern and DNA binding specificity is determined by the number of spacer nucleotides present between two direct repeats, everted repeats, or inverted repeats of the canonical binding sequence 5’-PuGGTCA. RXR/RAR heterodimers bind the Retinoic Acid Response Element (RARE) with a consensus half site separated by 2 or 5 nucleotides (DR2 or DR5) whereas RXR homodimers bind the Retinoid X Response Element (RXRE) which is separated by only one nucleotide (DR1). Selective response element recognition is due to a short sequence (the P box) located at the Cterminal base of the N-terminal C1 finger of the DNA Binding Domain (DBD) which interacts with the binding motif and to a weak dimerization function which encompases the N-terminal base of the CII finger (D-box) of the DBD. While RXR/RAR heterodimers bind more effectively to the RAREs than RXR homodimers, RXRs homodimers can bind RXREs with high affinity. RAREs can overlap with RXREs and since RXR/RAR heterodimers bind with a higher affinity than RXR homodimers, this may interfere with retinoid X receptor signaling.