Retinoic acid receptor binding domains

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

Retinoid action depends on binding to both cytosolic and nuclear retinoic acid receptors (RARs). RARs have distinct DNA and retinoid-binding domains, and they function as pairs and bind to the retinoic acid receptor element (RARE) to regulate transcriptional activity. 

B Thyroid hormone receptor, THR All-trans retinoic acid receptor, RAR Vitamin D3 receptor, VDR 9-c/s retinoic acid receptor, RXR, Peroxysome proliferator activating receptor, PPAR Orphan receptors Short A/B domains do not associate with chaperones. Unliganded receptors bind to DNA... 

Fig. 11.11 Structure of a fraction (residues 178-423) of the ligand-binding domain of the human retinoic acid receptor, RARy bound to aittians retinoic acid. The Igand, alttrans retinoic acid, is shown as a sdck-and-ball structure. The structure is typical of the ligandbinding domains of nuclear receptors in general. The 2.0 A crystal structure reveals the ligandbinding interactions. The overall fold of the binding pocket is similar to that of the human RXRa LBD. The ligandbinding pockets of the o,p,y- isoforms of RARs differ only in three residues. These three residues seem to be responsible for the differences between the three RAR subtypes. (Reproduced with permission of Professor D. Moras and Nature from the data in Fig. 1 of ref. 38. and the corresponding data available in protein databanks. See also ref. 39.)...

Tian, K., Norris, A.W., Lin, C.L. and Li, E. (1997) The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry, 36, 5669-5676. 

The understanding of the mechanism by which retinoids modulate gene expression implies that retinoids activate a signal-transduction pathway in which nuclear-retinoid receptors, which are members of the steroid hormone-receptor superfamily, play a pivotal role (14,16,18-22). Like other members of this family, the retinoid receptors are ligand-activated, DNA-binding transacting, transcription-modulating proteins. Two types of receptor have been identified retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each type includes three subtypes of RAR (a, p, and y) and of RXR (a, P, and y) with distinct ammo- and carboxy-terminal domains. RXR-RAR... 

Sasaki, T., Shimazawa, R., Sawada, T, Iijima, T, Fukasawa, H, Shudo, K, Hashimoto, Y., and Iwasaki, S (1995) Determination of the photoaffmity-labeled site on the ligand-binding domain of retinoic acid receptor a Biochem Biophys Res. Comm. 207, 444-451... 

Lamour FPY, Lardelli P, Apfel CM (1996) Analysis of the ligand-binding domain of human retinoic acid receptor a by site-directed mutagenesis. Mol Cell Biol 16 5386-5392... 

How does PPARy produce these responses Like other members of the nuclear receptor superfamily, PPARy contains a DNA-binding domain that recognizes hormone-responsive elements in the promoter regions of its target genes. Before binding to these sequences, however, PPARy must first combine with the 9-c/V-retinoic acid receptor, forming an active heterodimer (Fig. 5.2). ... 

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