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J. Biol. Chem., Vol. 281, Issue 31, 22236-22247, August 4, 2006

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Structural Determinants That Target the Hepatitis C Virus Core Protein to Lipid Droplets^*

Steeve Boulant, Roland Montserret, R. Graham Hope, Maxime Ratinier, Paul Targett-Adams, Jean-Pierre Lavergne, Francois Penin¹, and John McLauchlan²

From the Medical Research Council Virology Unit, Institute of Virology, Church St., Glasgow G11 5JR, Scotland, United Kingdom and the Institut de Biologie et Chimie des Protéines, CNRS-UMR 5086, IFR128 BioSciences, University of Lyon, 7 Passage du Vercors, Lyon-Gerland, Lyon F-69367, Cedex 07, France

Hepatitis C virus core protein is targeted to lipid droplets, which serve as intracellular storage organelles, by its C-terminal domain, termed D2. From circular dichroism and nuclear magnetic resonance analyses, we demonstrate that the major structural elements within D2 consist of two amphipathic -helices (Helix I and Helix II) separated by a hydrophobic loop. Both helices require a hydrophobic environment for folding, indicating that lipid interactions contribute to their structural integrity. Mutational studies revealed that a combination of Helix I, the hydrophobic loop, and Helix II is essential for efficient lipid droplet association and pointed to an in-plane membrane interaction of the two helices at the phospholipid layer interface. Aside from lipid droplet association, membrane interaction of D2 is necessary for folding and stability of core following maturation at the endoplasmic reticulum membrane by signal peptide peptidase. These studies identify critical determinants within a targeting domain that enable trafficking and attachment of a viral protein to lipid droplets. They also serve as a unique model for elucidating the specificity of protein-lipid interactions between two membrane-bound organelles.

Received for publication, February 2, 2006 , and in revised form, May 16, 2006.

^* This work was supported by the United Kingdom Medical Research Council (to J. M.), CNRS and University of Lyon, grants from Agence Nationale de Recherches sur le Sida (to J.-P. L. and F. P.) and from the ATC "hepatites" program of INSERM (to F. P.). 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 Fig. S1.

¹ To whom correspondence may be addressed. Tel.: 33-(0)4-72-72-26; Fax: 33-(0)4-72-72-26; E-mail: f.penin{at}ibcp.fr.

² To whom correspondence may be addressed. Tel.: 44-(0)141-330-4028; Fax: 44-(0)141-330-3520; E-mail: j.mclauchlan{at}vir.gla.ac.uk.

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