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

Cell Rep. 2016 Jun 7;15(10):2097-2108. doi: 10.1016/j.celrep.2016.04.088. Epub 2016 May 26.


Transcription 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Biological Evolution*
  • CREB-Binding Protein / chemistry
  • CREB-Binding Protein / metabolism
  • DNA-Activated Protein Kinase / metabolism
  • Forkhead Box Protein O1 / metabolism*
  • HeLa Cells
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / metabolism*
  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Mice
  • Models, Biological
  • Models, Molecular
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Transcriptional Activation / genetics


  • Forkhead Box Protein O1
  • Homeodomain Proteins
  • Hoxa11 protein, mouse
  • Intrinsically Disordered Proteins
  • CREB-Binding Protein
  • DNA-Activated Protein Kinase