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J. Biol. Chem., Vol. 282, Issue 37, 27306-27314, September 14, 2007

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Structure of the Ebola Fusion Peptide in a Membrane-mimetic Environment and the Interaction with Lipid Rafts^*

Mônica S. Freitas, Luciane P. Gaspar, Marcos Lorenzoni^¶, Fabio C. L. Almeida, Luzineide W. Tinoco^||, Marcius S. Almeida, Lenize F. Maia, Léo Degrève^¶, Ana Paula Valente, and Jerson L. Silva¹

From the Programa de Biologia Estrutural, Instituto de Bioquímica Médica, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, RJ, Departamento de Virologia, Instituto Oswaldo Cruz, Fiocruz, 21040-360 Rio de Janeiro, RJ, ^¶Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo 14040-901, Ribeirão Preto, S.P., and ^||Núcleo de Produtos Naturais, Laboratório de Analise e Desenvolvimento de Inibidores Enzimáticos, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, RJ, Brazil

The fusion peptide EBO₁₆ (GAAIGLAWIPYFGPAA) comprises the fusion domain of an internal sequence located in the envelope fusion glycoprotein (GP2) of the Ebola virus. This region interacts with the cellular membrane of the host and leads to membrane fusion. To gain insight into the mechanism of the peptide-membrane interaction and fusion, insertion of the peptide was modeled by experiments in which the tryptophan fluorescence and ¹H NMR were monitored in the presence of sodium dodecyl sulfate micelles or in the presence of detergent-resistant membrane fractions. In the presence of SDS micelles, EBO₁₆ undergoes a random coil-helix transition, showing a tendency to self-associate. The three-dimensional structure displays a 3₁₀-helix in the central part of molecule, similar to the fusion peptides of many known membrane fusion proteins. Our results also reveal that EBO₁₆ can interact with detergent-resistant membrane fractions and strongly suggest that Trp-8 and Phe-12 are important for structure maintenance within the membrane bilayer. Replacement of tryptophan 8 with alanine (W8A) resulted in dramatic loss of helical structure, proving the importance of the aromatic ring in stabilizing the helix. Molecular dynamics studies of the interaction between the peptide and the target membrane also corroborated the crucial participation of these aromatic residues. The aromatic-aromatic interaction may provide a mechanism for the free energy coupling between random coil-helical transition and membrane anchoring. Our data shed light on the structural "domains" of fusion peptides and provide a clue for the development of a drug that might block the early steps of viral infection.

Received for publication, December 28, 2006 , and in revised form, May 31, 2007.

The atomic coordinates and structure factors (code 2rlj) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Millennium Institute for Structural Biology in Biomedicine and Biotechnology (CNPq Millennium Program), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Rede Nacional de Biologia Molecular Estrutural, Financiadora de Estudos e Projetos of Brazil, and by an international grant from the International Centre for Genetic Engineering and Biotechnology (to J. L. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S-4S.

¹ To whom correspondence and reprint requests should be addressed. Tel.: 2562-6756; Fax: 55-21-2270-8647; E-mail: jerson{at}bioqmed.ufrj.br.

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