ReviewRetinoid X receptor and its partners in the nuclear receptor family
Introduction
Lipophilic hormones exert genetic control through a superfamily of highly related transcription factors known as the nuclear receptors. Included in this family are many additional factors, known as orphan receptors, which have the hallmarks of bona fide hormone receptors, but whose bioactive ligands have not been identified at this time. Although most frequently isolated and characterized in mammals, homologs of the hormone and orphan receptors have also been identified in insects, worms and amphibians. Transcription regulation by both the hormone and orphan receptors depends on specific and ordered interactions with DNA and on subsequent binding of co-repressor and/or co-activator proteins 1., 2., 3..
The DNA targets of nuclear receptors, known as response elements, are the sequences through which receptors mediate the control of ligand-responsive genes. Most nonsteroid and orphan receptors recognize the consensus sequence 5′-AGGTCA-3′ in DNA that contains one or two copies of this sequence. This group includes nearly all known nonsteroid receptors, including the 9-cis retinoic acid receptor (retinoid X receptor, RXR), the all-trans retinoic acid receptor (RAR), the thyroid hormone receptor (TR), the vitamin D receptor (VDR), the peroxisome proliferator-activated receptor (PPAR) and nerve growth factor induced-B (NGFI-B) 4., 5.. The receptors for glucocorticoids, mineralcorticoids, androgens and progesterone constitute a smaller subgroup not discussed here, which recognizes the consensus sequence 5′-AGAACA-3′ instead.
The nuclear receptor DNA-binding domain (DBD) is one of the most prevalent DNA-interacting regions known. It is composed of a highly conserved 66 amino acid core domain located centrally in each nuclear receptor, together with a short, nonconserved extension into the hinge region of the receptor (see Fig. 1) 6., 7.. Its modular design is composed of two zinc-binding loops and a pair of α helices 8. One of these helices mediates sequence-specific recognition of the AGGTCA sequence via major groove contacts. The sequence conservation of the DBD, together with the wide use of the AGGTCA response element sequence, raises the question as to how diversity is generated in this superfamily of transcription factors. In fact, considerable response element diversity is generated by taking the two AGGTCA sites and positioning them relative to each other in numerous geometrical arrangements to produce binding sites for various receptor homodimers and heterodimers. This review will focus on how dimerization patterns between the DBDs of RXR and its partners produce combinatorial transcription factors that are highly selective for their DNA response elements.
The major advances of the past year include two new crystal structures of DNA-binding complexes involving RXR: one of an RXR homodimer bound to direct repeat (DR) 1 DNA 9 and the other of the RXR–RAR heterodimer bound to DR1 10. These structures, together with earlier structures of the RXR–TR complex bound to DR4 11, the RevErb DBD homodimer bound to DR2 12 and the NGFI-B DBD monomer bound to an extended half-site 13, allow us to see the depth of variety by which nuclear receptors form highly selective surfaces for DNA binding. These structures are nicely complemented by additional studies that examine conformational changes in the DBD polypeptide as it binds DNA, showing the importance of conformational flexibility and induced structures in the formation of highly specific DNA-binding complexes 14, 15..
Section snippets
The rules of engagement
RXR is a combinatorial partner in the nuclear receptor family, able to form heterodimers with a variety of hormone and orphan receptors 16., 17., 18., 19.. The dimerization partners of RXR include itself, RAR, VDR, TR, PPAR and other receptors shown in Fig. 2. Importantly, the DBDs of RXR and its heterodimeric partners do not interact in the absence of response elements. However, in the presence of response elements, they produce the same patterns of DNA selectivity and dimerization as the
Structures of DNA-binding complexes
Three different co-crystal structures of DNA-binding complexes involving RXR are now available (see Fig. 3). The first glimpse of how RXR mediates heterodimeric binding of other receptors on DR elements came from the the structure of the RXR–TR DNA-binding complex on DR4 11. The asymmetrical head-to-tail placement of the subunits fosters productive interactions between subunits only when RXR occupies the 5′ half-site and TR occupies the 3′ half-site. Contacts between the two DBDs straddle the
The role of induced structures
The correctly spaced response element itself fosters heterodimerization between DBDs of RXR and its partners. This mechanism ensures efficiency in the nuclear receptor family by not requiring the formation of all possible tightly associated dimers in the absence of their gene regulatory sites 31. Effective interaction between subunits implies that each DBD must remain simultaneously engaged to its partner and to its own AGGTCA binding site. To understand how the DNA spacing can effect subunit
Conclusions
The structures of RXR DNA-binding complexes illustrate the remarkable versatility of transcription factors in forming combinatorial interactions that rely on the architecture of the DNA response elements. These studies have provided important new examples of how flexible surfaces on macromolecules can be precisely altered to facilitate the assembly of transcription factors on DNA. The lessons provided by these studies are likely to be shared with other transcription factor families that use
Acknowledgements
The author thanks Qiang Zhao for assistance with the figures and Sepideh Khorasanizadeh for critical reading of the manuscript. The author's work on DNA-binding complexes is supported by the National Institutes of Health.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
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2016, Journal of Biological ChemistryCitation Excerpt :Such heterodimers are highly abundant across organisms and exert essential molecular functions (2, 7, 8). Consequently, a lot of effort has been invested to determine their DNA binding specificities using various in vitro and in vivo approaches (7, 9–15). Several studies demonstrated the ability of two TFs to cooperate on DNA elements and thus provide an alternative mode of DNA recognition (16, 17).