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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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00370371
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Submitted on : Tuesday, March 24, 2009 - 11:19:16 AM
Last modification on : Tuesday, August 18, 2020 - 2:36:02 PM

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Catherine Tisné, Muriel Delepierre, Brigitte Hartmann. How NF-kappaB can be attracted by its cognate DNA.. Journal of Molecular Biology, Elsevier, 1999, 293 (1), pp.139-50. ⟨10.1006/jmbi.1999.3157⟩. ⟨pasteur-00370371⟩

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