title: Energetic coupling along an allosteric communication channel drives the binding of Jun-Fos heterodimeric transcription factor to DNA.
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.
authors.affiliation: Department of Biochemistry & Molecular Biology and USylvester Braman Family Breast Cancer Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Seldeen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Deegan
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhat
authors.forename: David C
authors.initials: DC
authors.lastname: Mikles
authors.forename: Caleb B
authors.initials: CB
authors.lastname: McDonald
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D004247:DNA