Conservation of hydrophobicity within viral envelope glycoproteins reveals a putative hepatitis C virus fusion peptide.
The mechanism(s) by which hepatitis C virus (HCV) enters and infects cells remains unknown. Identifying the HCV fusion peptide(s) and understanding the early stages of infection may provide new opportunities for improved antiviral therapy. The HCV envelope glycoprotein E2 is thought to be a class II fusion protein. Class II fusion proteins are exemplified by the E protein of the tick-borne encephalitis virus (TBEV) and the E1 protein of the Semliki Forest virus (SFV). Analysis of the hydrophobicity profiles of four HCV E2 envelope glycoproteins revealed a region with a conserved three-pronged pattern of hydrophobicity, termed the tridentate (TD) region. The primary sequence of the TD region is highly conserved in all 490 HCV strains currently reported. The known fusion peptide loops of TBEV and SFV share the characteristic TD region hydrophobicity profile and significant sequence conservation in the TD region was identified in the E and E1 glycoproteins of members of the Flaviviridae and Togaviridae families, respectively. The HCV TD region peptides have membranotropic activity; in molecular dynamics (MD) simulations, the HCV TD region peptides insert into in a biomimetic bilayer in a similar manner to the TBEV fusion peptide and the peptides induce effective mixing of lipid membranes in a liposome fusion assay. Together these results indicate that the highly conserved TD region of the HCV E2 protein is a fusion peptide candidate and may be an important factor in the class II fusion mechanism.
Taylor
A
A
Department of Biochemistry, and Oxford Glycobiology University of Oxford, South Parks Road, Oxford, OX1 3QU. ataylor@biop.ox.ac.uk
O'Leary
J M
JM
Pollock
S
S
Zitzmann
N
N
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D016174:Hepacivirus / Q000378:metabolism* / Q000502:physiology; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010802:Phylogeny; D011487:Protein Conformation; D014035:Togaviridae; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000378:metabolism; D053586:Virus Internalization
D008081:Liposomes; D010455:Peptides; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; C091015:glycoprotein E2, Hepatitis C virus