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DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity

Science, 17 April 2009
Vol. 324, Issue 5925, p. 407-410
DOI: 10.1126/science.1164265

DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity

  1. Sebastiaan H. Meijsing1*,
  2. Miles A. Pufall1*,
  3. Alex Y. So1,2,
  4. Darren L. Bates3,
  5. Lin Chen3,
  6. Keith R. Yamamoto1,2,
  1. 1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  2. 2 Chemistry and Chemical Biology Program, University of California, San Francisco, CA 94107, USA.
  3. 3 Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
  1. To whom correspondence should be addressed. E-mail: yamamoto{at}cmp.ucsf.edu
  • * These authors contributed equally to this work.

  1. Fig. 1.

    GBSs differentially direct GR activity. (A) GBSs were cloned upstream of a minimal SV40 promoter driving luciferase. Transcriptional activities and binding affinities (humanGR-DBD 380 to 540) for each GBSs ± SEM are shown [number of independent experiments (n) ≥ 3]. KD, dissociation constant. (B) GBS-specific patterns of domain utilization. GBS reporters respond differentially to mutations in Dim (red, A477T), AF1 (yellow, E219K/F220L/W234R), and AF2 (green, E773R) domains. Fold induction by dex ± SEM (top) and percent induction by mutant GR relative to wild type (bottom) are shown (n ≥ 3). (C) Immunoblots demonstrating short hairpin–mediated RNA (shRNA) knock-down of Brm and CARM1. (D) GBS inductions after CARM1 or Brm knock-down, relative to scrambled shRNA ± SEM, are shown (n = 3).

  2. Fig. 2.

    DNA sequence-mediated structural differences in GR-DBD. (A) Domain structure of GR. τ1, tau1. (B) Overlay of chains A and B from GR-DBD:Pal complex shows packed and flipped conformations. (C) Overlay of chain B from GR-DBD complexed with 4-bp spacer (15) (magenta) and 3-bp spacer GBS (green). (D) Composite omit maps of GR-DBD complexed with different GBSs (GilZ, FKBP5, Sgk, and Pal) under the same conditions. Lever arm peptide is shown with 2Fo-Fc (black mesh) and composite omit map (red mesh) overlaid.

  3. Fig. 3.

    Activities and structure of GRγ. (A) GRγ amino acid sequence, showing Arg insertion in the lever arm. (B) U2OS cells were cotransfected with GRα or GRγ, together with GBS reporters (left) or with an osteocalcin reporter (right). Fold induction (left) and luciferase activity relative to untreated cells (right) ± SEM are shown (n = 3). (C) Regulation of endogenous target genes in U2OS cells stably expressing GRα or GRγ, measured by quantitative real-time fluorescence polymerase chain reaction. (D) Chromatin immunoprecipitation of GR at GBSs of isoform-specific target genes; GR recruitment upon dex treatment ± SEM is shown (n = 3). (E) Overlay of structures for GRα:FKBP5 and GRγ:FKBP5 complexes.

  4. Fig. 4.

    Receptor activity is modulated by lever arm residues. (A) H472 is critical for tuning activity. Effects of mutating lever arm residues were assayed using GBS reporters; activities are plotted as percentage of wild type ± SEM (n ≥ 3). (B) H472 resides in the DBD pocket formed by the carbonyl adjacent to V468, Y497, and L501. (C) Human DBD sequence alignments reveal variation at V468, Y497, and L501.

Citation:

S. H. Meijsing, M. A. Pufall, A. Y. So, D. L. Bates, L. Chen, and K. R. Yamamoto, DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity. Science 324, 407-410 (2009).

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