title: Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity.
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.
authors: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, Ihnestrasse 63-73, Berlin 14195, Germany.
authors: Stefanie
authors: S
authors: Schöne
authors: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, Ihnestrasse 63-73, Berlin 14195, Germany.
authors: Marcel
authors: M
authors: Jurk
authors: Institute of Theoretical Physics, Free University Berlin, 14195 Berlin, Germany.
authors: Mahdi Bagherpoor
authors: MB
authors: Helabad
authors: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors: Iris
authors: I
authors: Dror
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Biologie Structurale, 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, BP 10142, 67404 Illkirch Cedex, France.
authors: Isabelle
authors: I
authors: Lebars
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Biologie Structurale, 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, BP 10142, 67404 Illkirch Cedex, France.
authors: Bruno
authors: B
authors: Kieffer
authors: Institute of Theoretical Physics, Free University Berlin, 14195 Berlin, Germany.
authors: Petra
authors: P
authors: Imhof
authors: Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors: Remo
authors: R
authors: Rohs
authors: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, Ihnestrasse 63-73, Berlin 14195, Germany.
authors: Martin
authors: M
authors: Vingron
authors: 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, F-75005 Paris, France.
authors: Morgane
authors: M
authors: Thomas-Chollier
authors: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, Ihnestrasse 63-73, Berlin 14195, Germany.
authors: Sebastiaan H
authors: SH
authors: Meijsing
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics*; D006801:Humans; D000072417:Protein Domains / Q000235:genetics; D020836:Protein Structure, Quaternary / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics
chemical_list: D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D004247:DNA