In a heterologous expression system, processed E1 and E2 remain

In a heterologous expression system, processed E1 and E2 remain

noncovalently associated, interacting in part through their C-terminal transmembrane domains, which also mediate retention of the E1-E2 complex in the ER (27). In addition, it has been demonstrated that E1 is able to adopt a polytopic topology, in which a heterodimeric noncovalent association with E2 is retained (31). E1 also interacts with Core, its interaction being dependent on oligomerization of Core (32). A recent study has demonstrated check details that the oligomeric state of E1 and E2 changes dramatically after incorporation into viral particles, upon which the virion-associated glycoproteins form large covalent complexes stabilized by disulfide bridges (28). As with related viruses, the mature HCV virion probably consists of a nucleocapsid, where Depsipeptide in vitro Core encapsidates and protects the viral genome and there is an outer envelope composed of a lipid membrane and envelope proteins. However, at present little is known about the molecular mechanisms for assembly of Core into nucleocapsids. Several heterologous expression systems have been used to investigate HCV capsid assembly (33–38). In vitro studies with recombinant proteins have revealed

that domain II and III of Core are dispensable for assembly (33, 34). C-terminally truncated Core (a.a. 1–124) and structured RNA have been implicated in nucleocapsid formation that produces homogenous spherical HCV particles. When Core containing the C terminus up to a.a. 174 has been similarly examined, a heterogeneous array of irregularly shaped

particles has been observed, suggesting that the C-terminus of the protein influences self-assembly. Removal of either cluster of basic residues located in domain I significantly reduces capsid assembly. In contrast, mutations of neutral residues exhibit no effect on assembly (39). However, RNA encapsidation is not specific under these conditions. Nucleocapsid assembly generally involves oligomerization of the capsid protein and encapsidation of genomic RNA. It has been shown that self-oligomerization of Core is promoted by a.a. 72 to 91 of the core protein (32). The encapsidation process is thought to occur upon interaction of Core with viral RNA, and the Core-RNA Non-specific serine/threonine protein kinase interaction may be critical for switching from RNA replication to packaging. Although the signal(s) and processes that mediate RNA packaging during HCV replication are largely unclear, it has been found that Core can bind to positive-strand HCV RNA through stem-loop domains I, III and nt 24–41 (40). Taken together, these model systems demonstrate that expression of HCV Core is sufficient to assemble into capsid-like structures in the presence of RNA. Since a tissue culture system for producing infectious HCV became available (41–43), findings on biochemical and ultrastructural properties of HCV particles, as well as key factors that are important for virion production, have been accumulating.

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