Charged residues in the transmembrane domains of hepatitis C virus glycoproteins play a major role in the processing, subcellular localization, and assembly of these envelope proteins

For most membrane proteins, the transmembrane domain (TMD) is more than jus t an anchor to the membrane. The TMDs of hepatitis C virus (HCV) envelope p roteins E1 and E2 are extreme examples of the multifunctionality of such me mbrane-spanning sequences, Indeed, they possess a signal sequence function in their C terminal half, play a major role in endoplasmic reticulum locali zation of El and E2, and are potentially involved in the assembly of these envelope proteins. These multiple functions are supposed to be essential fo r the formation of the viral envelope. As for the other viruses of the fami ly Flaviviridae, these anchor domains are composed of two, stretches of hyd rophobic residues separated by a short segment containing at least one full y conserved charged residue. Replacement of these charged residues by an al anine in HCV envelope proteins led to an alteration of all of the functions performed by their TMDs, indicating that these functions are tightly linke d together. These data suggest that the charged residues of the TMDs of HCV glycoproteins play a key role in the formation of the viral envelope.