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

Mauris C Nnamani; Soumya Ganguly; Eric M Erkenbrack; Vincent J Lynch; Laura S Mizoue; Yingchun Tong; Heather L Darling; Monika Fuxreiter; Jens Meiler; Günter P Wagner

doi:10.1016/j.celrep.2016.04.088

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.

Authors

Affiliations

¹ Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA.
² Departments of Chemistry, Pharmacology and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
³ Department of Human Genetics, The University of Chicago, 920 E. 58th Street, CLSC 319C, Chicago, IL 60637, USA.
⁴ Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80303, USA.
⁵ MTA-DE Momentum Laboratory of Protein Dynamics, University of Debrecen, 4032 Debrecen, Nagyerdei krt 98, Hungary.
⁶ 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.
⁷ 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.

PMID: 27239043
DOI: 10.1016/j.celrep.2016.04.088

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.

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

Substances

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