title: Molecular mechanisms of cooperative binding of transcription factors Runx1-CBFβ-Ets1 on the TCRα gene enhancer.
abstract: Ets1 is an essential transcription factor (TF) for several important physiological processes, including cell proliferation and differentiation. Its recognition of the enhancer region of the TCRα gene is enhanced by the cooperative binding of the Runx1-CBFβ heterodimer, with the cancelation of phosphorylation-dependent autoinhibition. The detailed mechanism of this interesting cooperativity between Ets1 and the Runx1-CBFβ heterodimer is still largely unclear. Here, we investigated the molecular mechanisms of this cooperativity, by using molecular dynamics simulations. Consequently, we detected high flexibility of the loop region between the HI2 and H1 helices of Ets1. Upon Runx1-CBFβ heterodimer binding, this loop transiently adopts various sub-stable conformations in its interactions with the DNA. In addition, a network analysis suggested an allosteric pathway in the molecular assembly and identified some key residues that coincide with previous experimental studies. Our simulations suggest that the cooperative binding of Ets1 and the Runx1-CBFβ heterodimer alters the DNA conformation and induces sub-stable conformations of the HI2-H1 loop of Ets1. This phenomenon increases the flexibility of the regulatory module, including the HI2 helix, and destabilizes the inhibitory form of this module. Thus, we hypothesize that this effect facilitates Ets1-DNA binding and prevents the phosphorylation-dependent DNA binding autoinhibition.
authors.affiliation: College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Fukuda
authors.affiliation: Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism*; D019673:Genes, T-Cell Receptor alpha / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D050784:Proto-Oncogene Protein c-ets-1