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Journal of Virology, February 2002, p. 1944-1958, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128'JVI.76.4.1944-1958.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Analysis of the C-Terminal Membrane Anchor Domains of Hepatitis C Virus Glycoproteins E1 and E2: toward a Topological Model

Benoit Charloteaux,1 Laurence Lins,1 Henri Moereels,2 and Robert Brasseur1*

Centre de Biophysique Moléculaire Numérique, Faculté Universitaire des Sciences Agronomiques de Gembloux, B-5030 Gembloux,1 Innogenetics, B-9052 Ghent, Belgium2

Received 18 June 2001/ Accepted 18 October 2001

The hepatitis C virus (HCV) glycoproteins E1 and E2 should be anchored in the viral membrane by their C-terminal domains. During synthesis, they are translocated to the endoplasmic reticulum (ER) lumen where they remain. The 31 C-terminal residues of the E1 protein and the 29 C-terminal residues of the E2 protein are implicated in the ER retention. Moreover, the E1 and E2 C termini are implicated in E1-E2 heterodimerization. We studied the E1 and E2 C-terminal sequences of 25 HCV strains in silico using molecular modeling techniques. We conclude that both C-terminal domains should adopt a similar and peculiar configuration: one amphipathic {alpha}-helix followed by a pair of transmembrane ß-strands. Several three-dimensional (3-D) models were generated. After energy minimization, their ability to interact with membranes was studied using the molecular hydrophobicity potentials calculation and the IMPALA procedure. The latter simulates interactions with a membrane by a Monte Carlo minimization of energy. These methods suggest that the ß-hairpins could anchor the glycoproteins in the ER membrane at least transiently. Anchoring could be stabilized by the adsorption of the nearby amphipathic {alpha}-helices at the membrane surface. The 3-D models correlate with experimental results which indicate that the E1-E2 transmembrane domains are involved in the heterodimerization and have ER retention properties.

* Corresponding author. Mailing address: Centre de Biophysique Moléculaire Numérique, Faculté Universitaire des Sciences Agronomiques de Gembloux, Passage des Déportés 2, B-5030 Gembloux, Belgium. Phone: 32.81.622.521. Fax: 32.81.622.522. E-mail: brasseur.r&{at}fsagx.ac.be.

Journal of Virology, February 2002, p. 1944-1958, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128'JVI.76.4.1944-1958.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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