Nuclear receptor Heterodimer

The structure of Rastinejad etal (Plate 24) shows how the DNA provides a scaffold for the asymmetrical dimerization of the DBDs of RXR and THR. This interface involves the carboxy-terminal extension of the DNA-binding domain of THR. This arrangement gives a clue to how nuclear receptor heterodimers recognize the spacings between DNA repeats and can distinguish between closely related response elements. 

Kurokawa, R, Yu, V C., Naar, A., Kyakumoto, S., Han, Z, Silverman, S, Rosenfeld, M G, and Glass, C. K (1993) Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers Genes Dev 7,1423-1435... 

Westin S, Kurokawa R, Nolte RT, Wisely GB, Mclnemey EM, Rose DW, Milbum MV, Rosenfeld MG, Glass CK (1998) Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 395 198-202... 

In summary, a DNA-supported asymmetric interface located within the DNA-binding domains of these nuclear receptors provides the molecular basis for receptor heterodimers to distinguish between closely related response elements. RXR can provide a repertoire of different dimerization surfaces, each one unique for a specific partner, allowing dimers to form that are adapted to the length of the spacer region in their corresponding response elements. 

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

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... 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Fig. 4.4. The principle of signal transduction by nuclear receptors. Nuclear receptors are ligand-controlled transcription factors that bind cognate DNA sequences, or hormone responsive elements (HRE). The hormone acts as a regulating ligand. Most nuclear receptors bind their cognate HREs, which tend to be symmetrically organized, as homo- or heterodimers. The DNA-bound, activated receptor stimulates transcription initiation via direct or indirect protein-protein interactions with the transcription initiation complex. The arrows demonstrate the different possible configurations of the HRE (see also 4.6). H hormone Hsp heat shock protein.

The receptors bind to the cognate HRE mainly as dimers, allowing the formation of homodimers as well as heterodimers between various receptor monomers. We know of very few nuclear receptors whose HRE contains only a single copy of the recognition sequence. These receptors bind as monomers to the cognate HRE. 

The DNA binding element of the nuclear receptors for all-trans retinoic acid, for 9-cis retinoic acid, for the T3 hormone and for the vitamin D3 hormone usually exhibit a direct repeat of the recognition sequence, resulting in formation of heterodimers on the DNA (fig. 4.7b). One of the partners in the heterodimer is always the receptor for 9-cis retinoic acid, RXR, and which usually occupies the 5 side of the HRE. 

Glass, C. Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers (1994) Endocrine Rev. 15, 391-407... 

Figure 9.10 Illustration depicting DNA elements found in CYP3A genes and the activation of the human pregnane X receptor (PXR) by ligand (RIF) and subsequent transcriptional activation of CYP3A4 gene by the PXR/RXR heterodimer. dNR-1-3, nuclear receptors 1, 2, and 3, respectively PXR, pregnane X receptor RXR, retinoid X receptor RIF, rifampicin SRC-1, steroid receptor co-activator XREM, xenobiotic responsive enhancer module.

Vitamin A has a very important role in regulating the actions of other hormone- and nutrient-dependent genes because the RXRs can interact with other nuclear receptors to form heterodimers that are able to bind and regulate hormone and nutrient responsiveness. The RXRs are able to heterodimerize with the vitamin D receptor, the thyroid hormone receptors, the peroxisome proliferator activated... 

Figure 29-6. Gene transcription is regulated by retinoic acid.Ah-Zrwm-retinoic acid and 9-cA-retinoic acid are ligands for retinoic acid receptors (RARs) and retinoid X receptors (RXRs), respectively. The RXRs can form heterodimers with RARs and with the thyroid hormone receptors (TRs), the vitamin D receptor (VDR), and the peroxisome proliferator-activated receptors (PPARs) and a number of other hormone- and nutrient-responsive transcription factors to moderate gene transcription. Because of the ability of RXR to form heterodimers with other nuclear receptors, vitamin A has abroad effect on many hormonally and nutrient-responsive genes.

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