The origin of nuclear receptor proteins: a single precursor distinct from other transcription factors.

Nuclear receptor proteins regulate transcription under the influence of hormones or other small ligands. These proteins bind to specific DNA sequences, termed hormone response elements (HREs), that reside close to hormone-responsive genes (reviewed in Ref. 1). This signal transduction process involves three discernible domains in the nuclear receptor proteins (reviewed in Refs. 2, 3)-the N-terminus, the central DNA-binding domain comprised of two zinc finger motifs, and the Cterminal ligand-binding domain; only the N-terminus is not well conserved. In general, virtually nothing is known about the origin of transcriptional regulatory factors. With respect to the nuclear receptor proteins in particular, two evolutionary histories have bean proposed. The first assumes independent origins for the different domains. By this view, ligand-binding segments with functions in bioenergetics and intermediary metabolism became fused to a DNAbinding motif to produce transcription factors, and the cell acquired the ability to respond at the transcriptional level to fluctuations in its physiological state (1). The second model implicates a single, multi-domain precursor that initially mediated a simple signal transduction mechanism (perhaps similar to that employed by the modem thyroid receptors) and subsequently acquired