There Is a Large Family of Nuclear Receptor Proteins
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
3rd edition , p520-521
2025-12-06
13
The nuclear receptor superfamily consists of a diverse set of transcription factors that were discovered because of a sequence similarity in their DBDs. This family, now with more than 50 members, includes the nuclear hormone receptors discussed earlier, a number of other receptors whose ligands were discovered after the receptors were identified, and many putative, or orphan receptors, for which the regulatory physiologic ligand has yet to be discovered.
These nuclear receptors have several common structural features (Figure 1). All have a centrally located DBD that allows the receptor to bind with high affinity to its cognate HRE. The DBD contains two zinc finger binding motifs that direct binding either as homodimers, as heterodimers (usually with a retinoid X receptor [RXR] partner), or as monomers. The target response element consists of one or two DNA half-site consensus sequences arranged as an inverted or direct repeat. The spacing between the latter helps determine binding specificity. Thus, in general, a direct repeat with three, four, or five nucleotide spacer regions specifies the binding of the vitamin D, thyroid, and retinoic acid receptors, respectively, to the same consensus response element. A multifunctional ligand-binding domain (LBD) is located in the carboxyl terminal half of the receptor. The LBD binds hormones or metabolites with selectivity and thus specifies a particular biologic response. The LBD also contains domains that mediate the binding of heat shock proteins, dimerization, nuclear localization, and transactivation. The latter function is facilitated by the carboxyl-terminal transcription activation function, or activation domain/AD (AF-2 domain), which forms a surface required for the inter action with coactivators. A highly variable hinge region separates the DBD from the LBD. This region provides flexibility to the receptor, so it can assume different DNA-binding con formations. Finally, there is a highly variable amino-terminal region that contains another AD referred to as AF-1. The AF-1 AD likely provides for distinct physiologic functions through the binding of different coregulator proteins. This region of the receptor, through the use of different promoters, alternative splice sites, and multiple translation initiation sites, pro vides for receptor isoforms that share DBD and LBD identity but exert different physiologic responses because of the association of various coregulators with this variable amino terminal AF-1 AD.
Fig1. The nuclear receptor superfamily. Members of this family are divided into six structural domains (A-F). Domain A/B is also called AF-1, or the modulator region, because it contains an AD and is involved in activating transcription. The C domain consists of the DNA-binding domain (DBD). The D region contains the hinge, which provides flexibility between the DBD and the ligand-binding domain (LBD, region E). The C-terminal part of region E contains AF-2, another AD that also contributes importantly to activation of transcription. The F region is less well defined. The functions of these domains are discussed in more detail in the text. Receptors with known ligands, such as the steroid hormones, bind as homodimers on inverted repeat half-sites. Other receptors form heterodimers with the partner RXR on direct repeat elements. There can be nucleotide spacers of one to five bases between these direct repeats (DR1-5). Another class of receptors for which ligands have not been definitively determined (orphan receptors) bind as homodimers to direct repeats and occasionally as monomers to a single half-site.
It is possible to sort this large number of receptors into groups in a variety of ways. Here, they are discussed according to the way they bind to their respective DNA elements (see Figure 1). Classic hormone receptors for glucocorticoids (GR), mineralocorticoids (MR), estrogens (ER), androgens (AR), and progestins (PR) bind as homodimers to inverted repeat sequences. Other hormone receptors such as thyroid (TR), retinoic acid (RAR), and vitamin D (VDR) and receptors that bind various metabolite ligands such as PPAR α, β, and γ, FXR, LXR, PXR, and CAR bind as heterodimers, with RXR as a partner, to direct repeat sequences (see Figure1 and Table 1). Another group of orphan receptors that as yet have no known ligand bind as homodimers or monomers to direct repeat sequences.
Table1. Nuclear Receptors With Special Ligands a
As illustrated in Table 1, the discovery of the nuclear receptor superfamily has led to an important understanding of how a variety of metabolites and xenobiotics regulate gene expression and thus the metabolism, detoxification, and elimination of normal body products and exogenous agents such as pharmaceuticals. Not surprisingly, this area is a fertile field for investigation of new therapeutic interventions.
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