Heterodimers, retinoid receptors

CRABP (1) and CRABP (11) function to transport retinoic acid into the nucleus for binding to retinoid receptors. CRABP(ll), with retinoic acid bound, also interacts directly with the liganded RAR-RXR heterodimer bound to hormone response elements on DNA and enhances the activity of the nuclear receptor (Section2.3.2.1 Delvaetal., 1999). 

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. 

Thus, when a drug activates PXR it then binds as a heterodimer with the orphan retinoid receptor (RXR) to the promoter region of the CYP3A4 gene, thus enhancing its transcription [43]. 

The ligands for several of the nuclear receptors, including VDR and retinoid receptors, are known to play a role in heterodimer interactions (2,23) as well as in the interaction of these receptors with other transcription factors (6,7,24). The two-hybrid system is well-suited to test the ligand dependence of nuclear receptor interactions with other proteins. 

The retinoid X receptor forms heterodimers that recognize tandem repeats with variable spacings... 

Shulman AI, Mangelsdorf DJ (2005) Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 353 604-615... 

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