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The Hepatitis C Virus RNA-Dependent RNA Polymerase Membrane Insertion Sequence Is a Transmembrane Segment

Department of Medicine II, University of Freiburg, D-79106 Freiburg,¹ Department of Molecular Virology, University of Heidelberg, D-69120 Heidelberg, Germany,² Institut de Biologie et Chimie des Protéines, CNRS-UMR 5086, F-69367 Lyon Cedex 07, France³

Received 17 June 2002/ Accepted 3 September 2002

The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) belongs to a class of membrane proteins termed tail-anchored proteins. Here, we show that the HCV RdRp C-terminal membrane insertion sequence traverses the phospholipid bilayer as a transmembrane segment. Moreover, the HCV RdRp was found to be retained in the endoplasmic reticulum (ER) or an ER-derived modified compartment both following transient transfection and in the context of a subgenomic replicon. An absolutely conserved GVG motif was not essential for membrane insertion but possibly provides a docking site for transmembrane protein-protein interactions. These findings have important implications for the functional architecture of the HCV replication complex.

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