The nuclear receptor Ftz-F1 and homeodomain protein Ftz interact through evolutionarily conserved protein domains

The Drosophila homeodomain protein Fushi Tarazu (Ftz) and its partner, the orphan receptor Ftz-F1. are members of two distinct families of DNA binding transcriptional regulators. Ftz and Ftz-F1 form a novel partnership in viv o as a Hox/orphan receptor heterodimer. Here we show that the murine Ftz-F1 ortholog SF-1 functionally substitutes for Ftz-F1 in vivo. rescuing the de fects of ftz-f1 mutants. This finding identified evolutionarily conserved d omains of Ftz-F1 as critical for activity of this receptor in vivo. These d omains function. at least in part. by mediating direct protein interactions with Ftz. The Ftz-F1 DNA binding domain interacts strongly with Ftz and dr amatically facilitates the binding of Ftz to target DNA. This interaction i s augmented by a second interaction between the AF-2 domain of Ftz-F1 and t he N-terminus of Ftz via an LRALL sequence in Ftz that is reminiscent of LX XLL motifs in nuclear receptor coactivators. We propose that Ftz-F1 serves as a cofactor for Ftz by facilitating the selection of target sites in the genome that contain Ftz/Ftz-F1 composite binding sites. Ftz, on the other h and, influences Ftz-F1 activity by interacting with its AF-2 domain in a ma nner that mimics a nuclear receptor coactivator. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.