Evolution of Conditional Cooperativity Between HOXA11 and FOXO1 Through Allosteric Regulation

SUMMARY Transcription factors (TFs) play multiple roles in different cells and stages of development. Given this multitude of functional roles it has been assumed that TFs are evolutionarily highly constrained. Here we investigate the molecular mechanisms for the origin of a derived functional interaction between two TFs that play a key role in mammalian pregnancy, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires an interaction with FOXO1, and that the physical interaction between these proteins evolved long before their functional cooperativity. Through a combination of functional, biochemical, and structural approaches, we demonstrate that the derived functional cooperativity between HOXA11 and FOXO1 is due to derived allosteric regulation of HOXA11 by FOXO1. This study shows that TF function can evolve through changes affecting the functional output of a pre-existing protein complex.