title: How NF-kappaB can be attracted by its cognate DNA.
abstract: NF-kappaB is involved in the transcriptional regulation of a large number of genes, in particular those of human immunodeficiency virus (HIV). Recently, we used NMR spectroscopy and molecular modelling to study the solution structure of a native duplex related to the HIV-1 kappaB site, together with a mutated duplex for which a three base-pair change abolishes NF-kappaB binding. The native duplex shows unusual dynamics of the four steps surrounding the kappaB site. Here, we explore the intrinsic properties of the NMR-refined structures of both duplexes in order to understand why the native sequence is recognised by NF-kappaB among other DNA sequences. We establish that only the native kappaB site can adopt a conformation where its structure (curvature and base displacement), the accessibility and the electrostatic potentials of key atoms become very favourable for binding the large loops of NF-kappaB, in contrast to the mutated duplex. Finally, we show that the neutralisation of phosphate groups contacted by NF-kappaB favours a more canonical DNA structure. These findings lead to a new hypothesis for specific recognition through the phosphodiester backbone dynamics of the sequences flanking a binding site. Such unusual behaviour confers upon the overall duplex properties that can be used by NF-kappaB to select its binding site. Thus, the selectivity determinants for NF-kappaB binding appear to depend on deformability of an "extended" consensus sequence.
authors.affiliation: Institut Pasteur, CNRS URA 1129, 28 rue du Docteur Roux, Paris, 75015, France. tisne@pasteur.fr
authors.forename: C
authors.initials: C
authors.lastname: Tisné
authors.forename: M
authors.initials: M
authors.lastname: Delepierre
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D005814:Genes, Viral; D015497:HIV-1 / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010710:Phosphates; D055672:Static Electricity
chemical_list: D016328:NF-kappa B; D010710:Phosphates; D004247:DNA