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J. Biol. Chem., Vol. 283, Issue 13, 8089-8101, March 28, 2008

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Identification of the Membrane-active Regions of Hepatitis C Virus p7 Protein

BIOPHYSICAL CHARACTERIZATION OF THE LOOP REGION^*

Ana J. Pérez-Berná¹, Jaime Guillén¹, Miguel R. Moreno, Angela Bernabeu, Georg Pabst, Peter Laggner², and José Villalaín²

From the Instituto de Biología Molecular y Celular, Universidad "Miguel Hernández," E-03202 Alicante, Spain and the Institute of Biophysics and Nanosystems Research, Austrian Academy of Sciences, Graz A-8042, Austria

We have identified the membrane-active regions of the hepatitis C virus p7 protein by performing an exhaustive study of membrane rupture, hemifusion, and fusion induced by a p7-derived peptide library on model membranes having different phospholipid compositions. We report the identification in p7 of a highly membranotropic region located at the loop domain of the protein. Here, we have investigated the interaction of a peptide patterned after the p7 loop (peptide p7_L), studying its binding and interaction with the lipid bilayer, and evaluated the binding-induced structural changes of the peptide and the phospholipids. We show that positively rich p7_L strongly binds to negatively charged phospholipids and it is localized in a shallow position in the bilayer. Furthermore, peptide p7_L exhibits a high tendency to oligomerize in the presence of phospholipids, which could be the driving force for the formation of the active ion channel. Therefore, our findings suggest that the p7 loop could be an attractive candidate for antiviral drug development, because it could be a target for antiviral compounds that may lead to new vaccine strategies.

Received for publication, November 16, 2007 , and in revised form, January 14, 2008.

^* This work was supported in part by Grant BFU2005-00186-BMC from the Ministerio de Ciencia y Tecnología, Spain (to J. V.). 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 Recipients of pre-doctoral fellowships from the Autonomous Government of the Comunidad Valenciana, Spain.

² To whom correspondence should be addressed: IBMC, Universidad "Miguel Hernández," E-03202 Alicante, Spain. Tel.: 34-966-658-762; Fax: 34-966-658-758; E-mail: jvillalain{at}umh.es.

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