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J. Biol. Chem., Vol. 279, Issue 46, 47968-47974, November 12, 2004

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Positive Contribution of Hydration on DNA Binding by E2c Protein from Papillomavirus^*

Luis Maurício T. R. Lima and Jerson L. Silva¶||

From the Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, CCS, Bss34, Ilha do Fundão, 21941-590 Rio de Janeiro and the ^¶Departamento de Bioquímica Médica, Centro Nacional de Ressonncia Magnética Nuclear de Macromoléculas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil

Protein-nucleic acid interactions are responsible for the regulation of key biological events such as genomic transcription and recombination and viral replication. However, the recognition mechanisms involved in these processes are not completely understood. Here, we investigate the dominant forces involved in protein-protein and protein-DNA interactions for the 80-amino-acid C-terminal domain of the E2 protein (E2c) from human papillomavirus (HPV-16). The E2c protein is a homodimer that specifically binds to double-stranded DNA containing the consensus sequence ACCG-N₄-CGGT, where N is any nucleotide. DNA binding affinity is reduced by lowering water chemical potential, accompanied by an increase in cooperativity. Wyman linkage relations between affinity and water chemical potential indicate that 11 additional water molecules are bound in the formation of the complex between E2c and DNA. Salt dissociation isotherms showed that 10 counterions are released upon association, even at low water activity, indicating that this latter variable does not change the electrostatic component of the interaction. Further analysis demonstrates a strong dependence of cooperativity of binding on the protein concentration. Altogether, these results reveal a novel binding pathway in which the consolidated complex may achieve its final form via a monomer-DNA intermediate, which favors the binding of a second monomer. This molecular mechanism reveals the contributions of multiple conformers in a tight virus genome modulation that seems to be important in the cell infection scenario.

Received for publication, July 8, 2004 , and in revised form, August 16, 2004.

^* This work was supported by grants (to L. M. T. R. L. and J. L. S.) from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa no Estado do Rio de Janeiro Prowex, and Fundação Universitária José Bonifácio. 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.

To whom correspondence may be addressed. Tel./Fax: 55-21-2564-7380; E-mail: mauricio{at}pharma.ufrj.br. || To whom correspondence may be addressed. Tel.: 55-21-2562-6761; E-mail: Jerson{at}bioqmed.ufrj.br.

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