Multiple parameters control the selectivity of nuclear receptors for their response elements. Selectivity and promiscuity in response element recognition by retinoic acid receptors and retinoid X receptors.

A number of nuclear receptors are capable of binding to specific DNA sequences known as response elements that correspond to two 5'-PuG(G/T)TCA motifs. We have systematically compared the selectivity of DNA sequence recognition by the estrogen receptor and the retinoic acid receptor (RAR) and retinoid X receptor (RXR), using a variety of synthetic oligonucleotides related to natural response elements. The importance of the spacing and relative orientation of the PuG(G/T)TCA motifs as well as the possible role of the flanking sequences were investigated for each receptor. We find that the three receptors have different response element preferences and that their intrinsic DNA binding properties cannot be simply ascribed to spacing or orientation rules. For example, RARs bind with similar efficiencies to response elements containing directly repeated PuGTTCA motifs separated by 2, 3, 4, or 5 base pairs, and RXRs bind to response elements in which the directly repeated motifs are separated by 1, 2, and 5 base pairs. The actual sequence of the repeated motifs and the nature of their flanking bases appear to be important parameters in determining RAR and RXR binding efficiencies. The possibility that the binding specificity of nuclear receptors can be modified by interactions with other proteins, in particular other nuclear receptors, is discussed in relation to the patterns of transcriptional activation observed with either endogenous or transiently expressed receptors on chimeric promoters containing various response elements.