Energetic coupling along an allosteric communication channel drives the binding of Jun-Fos heterodimeric transcription factor to DNA

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

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Although allostery plays a central role in driving protein-DNA interactions, the physical basis of such cooperative behavior remains poorly understood. In the present study, using isothermal titration calorimetry in conjunction with site-directed mutagenesis, we provide evidence that an intricate network of energetically-coupled residues within the basic regions of the Jun-Fos heterodimeric transcription factor accounts for its allosteric binding to DNA. Remarkably, energetic coupling is prevalent in residues that are both close in space, as well as residues distant in space, implicating the role of both short- and long-range cooperative interactions in driving the assembly of this key protein-DNA interaction. Unexpectedly, many of the energetically-coupled residues involved in orchestrating such a cooperative network of interactions are poorly conserved across other members of the basic zipper family, emphasizing the importance of basic residues in dictating the specificity of basic zipper-DNA interactions. Collectively, our thermodynamic analysis maps an allosteric communication channel driving a key protein-DNA interaction central to cellular functions in health and disease. Isothermal titration calorimetry in conjunction with site-directed mutagenesis is employed here to map an intricate network of energetically-coupled basic residues driving the allosteric binding of Jun-Fos heterodimeric transcription factor to DNA. Surprisingly, many of the energetically-coupled residues are poorly conserved across other members of the bZIP family, underscoring the importance of basic residues in dictating the specificity of bZIP-DNA interactions.

Original languageEnglish (US)
Pages (from-to)2090-2104
Number of pages15
JournalFEBS Journal
Volume278
Issue number12
DOIs
StatePublished - Jun 1 2011

Keywords

  • allosteric communication
  • AP1-DNA thermodynamics
  • cooperative binding
  • energetic coupling
  • isothermal titration calorimetry

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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