Estrogen receptor-related receptor gamma has an exceptionally broad specificity of DNA sequence recognition

Estrogen receptor-related receptors (ERRs) constitute a subfamily of the nuclear hormone receptor superfamily. ERRs are closely related to estrogen receptors (ERs), but apparently lack ligand dependence. In this study, we cloned rat ERRgamma as an interacting partner of an orphan nuclear receptor, small heterodimer partner (SHP). ERRgamma exhibited significant binding affinities with a wide spectrum of sequences: inverted and direct repeat motifs composed of AGGTCA half-sites with various spacings, as well as a monovalent motif of the same sequence carrying extra T(C/G)A trinucleotides on the 5' side. On the other hand, inverted repeat spaced by three nucleotides was dominantly efficient for the binding of ERalpha. These results were mostly consistent with those of gene reporter assays. ERRgamma bound as a homodimer to all binding sequences tested, including a monovalent binding site, and ERRgamma did not heterodimerize with ERalpha. Taken together, ERRgamma recognizes a tremendously broad range of sequences as a homodimer. Finally, we found that SHP efficiently represses the transcriptional activity of ERRgamma, even at a far lower concentration than that of ERRgamma.