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J. Biol. Chem., Vol. 281, Issue 51, 39236-39248, December 22, 2006

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Indirect Recognition in Sequence-specific DNA Binding by Escherichia coli Integration Host Factor

THE ROLE OF DNA DEFORMATION ENERGY^*

Kimberly A. Aeling¹, Michael L. Opel², Nicholas R. Steffen^¶2, Vira Tretyachenko-Ladokhina^||, G. Wesley Hatfield, Richard H. Lathrop^¶, and Donald F. Senear^||3

From the Institute for Genomics and Bioinformatics, Department of Microbiology and Molecular Genetics, School of Medicine, the ^¶Department of Computer Science, School of Information and Computer Sciences, and the ^||Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Califoria 92697

Integration host factor (IHF) is a bacterial histone-like protein whose primary biological role is to condense the bacterial nucleoid and to constrain DNA supercoils. It does so by binding in a sequence-independent manner throughout the genome. However, unlike other structurally related bacterial histone-like proteins, IHF has evolved a sequence-dependent, high affinity DNA-binding motif. The high affinity binding sites are important for the regulation of a wide range of cellular processes. A remarkable feature of IHF is that it employs an indirect readout mechanism to bind and wrap DNA at both the nonspecific and high affinity (sequence-dependent) DNA sites. In this study we assessed the contributions of pre-formed and protein-induced DNA conformations to the energetics of IHF binding. Binding energies determined experimentally were compared with energies predicted for the IHF-induced deformation of the DNA helix (DNA deformation energy) in the IHF-DNA complex. Combinatorial sets of de novo DNA sequences were designed to systematically evaluate the influence of sequence-dependent structural characteristics of the conserved IHF recognition elements of the consensus DNA sequence. We show that IHF recognizes pre-formed conformational characteristics of the consensus DNA sequence at high affinity sites, whereas at all other sites relative affinity is determined by the deformational energy required for nearest-neighbor base pairs to adopt the DNA structure of the bound DNA-IHF complex.

Received for publication, July 5, 2006 , and in revised form, October 10, 2006.

^* This work was supported in part by Grant NIH68903 from the National Institutes of Health (to G. W. H.) and Grant MCB-9728186 from the National Science Foundation (to D. F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a predoctoral fellowship.

² Recipient of postdoctoral fellowship from the Biomedical Informatics Training Program of the University of California, Irvine, Institute for Genomics and Bioinformatics.

³ To whom correspondence should be addressed. Tel.: 949-824-8014; Fax: 949-824-8551; E-mail: dfsenear{at}uci.edu.

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