Domain I, the N-terminal ∼120 residues, is highly basic and is probably involved in the recruitment of the viral RNA during particle formation. Domain II, situated between a.a.∼120 and ∼175, has been predicted to form one or two alpha-helices that are presumed to be involved in the association of Core with membrane proteins and lipids. This domain is not present in the capsid proteins of most of the other members of the Flaviviridae family. It has recently been shown that the cysteine residue at a.a.128 is responsible for the disulfide-bonded dimer of Core and for particle formation (19). Domain III, located at

the C-terminal ∼20 residues, is highly hydrophobic and has been predicted to form an alpha helix. This domain serves as a signal sequence GW-572016 chemical structure Acalabrutinib mouse for E1 as described above. The ubiquitin-proteasome pathway, a major route by which selective protein degradation occurs in eukaryotic cells, is involved

in post-translational modification of Core (20–25). Ubiquitin ligase E6AP has been identified as a core-binding protein that enhances its ubiquitylation and degradation. It has been suggested that E6AP-dependent degradation of Core is common to a variety of HCV isolates and plays a critical role in the HCV life cycle (23). Recently, we also demonstrated that proteasomal degradation of Core is mediated by two distinct mechanisms. One leads to polyubiquitylation in which lysine residues in the N-terminal region are preferential ubiquitylation sites. The other is ubiquitin-independent, ADP ribosylation factor but depends on interaction with proteasome activator PA28gamma (24). Although is so far unclear as to whether destabilization of Core via two distinct mechanisms is physiologically significant, it is reasonable to consider that tight control over cellular levels of Core may contribute to restricting its potential for functional activity. E1 and E2 proteins are essential

components of the virion envelope and are necessary for viral entry. These glycosylated proteins extend from a.a. 192–383 (E1) and from a.a. 384–746 (E2) of the polyprotein, and have molecular weights of 33–35 and 70–72 kDa, respectively (26). Intracellular envelope proteins mainly exhibit high-mannose type glycans, consistent with their accumulation in the ER (27), whereas infectious-virion-associated envelope proteins display a mixture of high-mannose and complex types of glycans. It has been shown that E1 and E2 are heavily glycosylated, suggesting that HCV glycoproteins are processed by Golgi-resident glycosidases and glycosyltransferases (28). Complex N-linked glycans have also been detected on the surface of HCV particles isolated from patient sera (29). Based on prediction of membrane topology, it is hairpin structures that pass through the membrane twice, thereby allowing processing by a signal peptide in the ER lumen (30).