Dimerization nuclear receptors

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. 

A typical nuclear receptor contains a domain responsible for the DNA binding (domain C), the ligand binding and dimerization (E), and for the transactivation and other protein-protein interactions (A,B,E,F). Furthermore, there are also nuclear localization signals (D). 

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 Ugand binding domain (section E in fig. 4.5) of the nuclear receptors harbors several functions. Apart from the specific binding site for the hormone, one finds further structural elements in this domain which mediates dimerization of the receptors as well as structural elements important for the ligand-mediated transactivation. 

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

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

While bound to its cognate response element, the liganded/dimerized receptor recruits co-activator proteins that link with additional transcription factors, often leading to acetylation of histones, which opens up the nucleo-some to admit RNA polymerase II to the transcription start site. As would be expected, given that there is a sizeable superfamily of nuclear receptors and numerous interacting proteins, this simplified central theme is subject to many variations and complexities that allow subtle fine-tuning of regulatory responses. 

The AhRR may stand as a unique repressor of DME induction by xenobiotics. No analogous inducible repressor is known to squelch DME induction by other nuclear receptors. However, members of the steroid receptor superfamily such as CAR, GR, LXR, PXR, etc., exhibit complex inhibitory or synergistic interactions because they alter each other s expression or because they compete for generic dimerization partners such as RXR. 

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

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. 

---