Genetic variations within the ERE motif modulate plasticity and energetics of binding of DNA to the ERα nuclear receptor

Brian J. Deegan, Vikas Bhat, Kenneth L. Seldeen, Caleb B. McDonald, Amjad Farooq

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Upon binding to estrogens, the ERα nuclear receptor acts as a transcription factor and mediates a multitude of cellular functions central to health and disease. Herein, using isothermal titration calorimetry (ITC) and circular dichroism (CD) in conjunction with molecular modeling (MM), we analyze the effect of symmetric introduction of single nucleotide variations within each half-site of the estrogen response element (ERE) on the binding of ERα nuclear receptor. Our data reveal that ERα exudes remarkable tolerance and binds to all genetic variants in the physiologically relevant nanomolar-micromolar range with the consensus ERE motif affording the highest affinity. We provide rationale for how genetic variations within the ERE motif may reduce its affinity for ERα by orders of magnitude at atomic level. Our data also suggest that the introduction of genetic variations within the ERE motif allows it to sample a much greater conformational space. Surprisingly, ERα displays no preference for binding to ERE variants with higher AT content, implying that any advantage due to DNA plasticity may be largely compensated by unfavorable entropic factors. Collectively, our study bears important consequences for how genetic variations within DNA promoter elements may fine-tune the physiological action of ERα and other nuclear receptors.

Original languageEnglish (US)
Pages (from-to)262-270
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume507
Issue number2
DOIs
StatePublished - Mar 15 2011

Keywords

  • Circular dichroism
  • Estrogen receptor α
  • Estrogen response element
  • Isothermal titration calorimetry
  • Molecular modeling
  • Nuclear receptors

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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