title: A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1.
abstract: 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.
authors.affiliation: Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Mauris C
authors.initials: MC
authors.lastname: Nnamani
authors.affiliation: Departments of Chemistry, Pharmacology and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Erkenbrack
authors.affiliation: Department of Human Genetics, The University of Chicago, 920 E. 58th Street, CLSC 319C, Chicago, IL 60637, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Lynch
authors.affiliation: Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80303, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Mizoue
authors.affiliation: Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Departments of Chemistry, Pharmacology and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Darling
authors.affiliation: MTA-DE Momentum Laboratory of Protein Dynamics, University of Debrecen, 4032 Debrecen, Nagyerdei krt 98, Hungary.
authors.forename: Monika
authors.initials: M
authors.lastname: Fuxreiter
authors.affiliation: Departments of Chemistry, Pharmacology and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jens.meiler@vanderbilt.edu.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA; Department of Obstetrics, Gynecology and Reproductive Science, Yale University Medical School, New Haven, CT 06510, USA; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA. Electronic address: gunter.wagner@yale.edu.
authors.forename: Günter P
authors.initials: GP
authors.lastname: Wagner
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D005075:Biological Evolution; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000071161:Forkhead Box Protein O1; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; D064267:Intrinsically Disordered Proteins; D050882:CREB-Binding Protein; D051747:DNA-Activated Protein Kinase