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Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity

Author

Listed:
  • Stefanie Schöne

    (Max Planck Institute for Molecular Genetics)

  • Marcel Jurk

    (Max Planck Institute for Molecular Genetics)

  • Mahdi Bagherpoor Helabad

    (Institute of Theoretical Physics, Free University Berlin)

  • Iris Dror

    (Molecular and Computational Biology Program, University of Southern California
    Present address: Department of Biological Chemistry, University of California, Los Angeles, California 90095, USA)

  • Isabelle Lebars

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS) UMR 7104/Institute National de la Santé et de la Recherche Médicale (INSERM) U964/Université de Strasbourg, 1 rue Laurent Fries)

  • Bruno Kieffer

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS) UMR 7104/Institute National de la Santé et de la Recherche Médicale (INSERM) U964/Université de Strasbourg, 1 rue Laurent Fries)

  • Petra Imhof

    (Institute of Theoretical Physics, Free University Berlin)

  • Remo Rohs

    (Molecular and Computational Biology Program, University of Southern California)

  • Martin Vingron

    (Max Planck Institute for Molecular Genetics)

  • Morgane Thomas-Chollier

    (Institut de Biologie de l'Ecole Normale Supérieure, Institut National de la Santé et de la Recherche Médicale, U1024, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8197)

  • Sebastiaan H. Meijsing

    (Max Planck Institute for Molecular Genetics)

Abstract

The glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes.

Suggested Citation

  • Stefanie Schöne & Marcel Jurk & Mahdi Bagherpoor Helabad & Iris Dror & Isabelle Lebars & Bruno Kieffer & Petra Imhof & Remo Rohs & Martin Vingron & Morgane Thomas-Chollier & Sebastiaan H. Meijsing, 2016. "Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12621
    DOI: 10.1038/ncomms12621
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