A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1

• The HOXA11 protein has a regulatory motif that masks its activation domain
• In placental mammals, upon binding to FOXO1, HOXA11 unmasks its activation domain
• In the ancestral HOXA11, binding to FOXO1 does not unmask the activation domain
• In placental mammals the HOXA11::FOXO1 complex evolved a neo-allosteric switch

SummaryTranscription factors (TFs) play multiple roles in development. Given this multifunctionality, 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, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires interaction with FOXO1, and that the physical interaction between these proteins evolved before their functional cooperativity. Here, 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.

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