|PROSITE documentation PDOC51693|
The hepatitis C virus (HCV) is the predominant member of the genus Hepacivirus [E1] in the family Flaviviridae. It is a major causative agent of acute and chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. The HCV genome is a single-stranded RNA encoding a polyprotein that includes two proteases essential for virus replication. The NS2 cysteine protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3 serine protease cleaves at four downstream sites in the polyprotein. Optimal processing at the NS2/3 junction appears to necessitate the presence of the NS3 serine protease domain as a structural unit but does not require its serine protease activity. NS2 is a 217 amino acids (aa) long cysteine-protease composed of a highly hydrophobic N-terminal membrane binding domain (MBD) and a C-terminal globular and cytosolic protease domain [1,2]. The HCV NS2 protease domain forms the peptidase family C18 [E2].
The structure of the HCV NS2 protease domain reveals a dimeric cysteine protease with two composite active sites (see <PDB:2HD0>). For each active site, the catalytic histidine and gluatamate residues are contributed by one monomer, and their nucleophilic cysteines by the other. The carboxy-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. The NS2 protease domain monomer consists of two subdomains connected by an extended linker. The amino-terminal subdomain contains two antiparallel α-helices (H1 and H2) followed by several turns and loops that contact both H1 and H2. The polypeptide continues into an extended region before entering a four-stranded, antiparallel β-sheet in the C-terminal subdomain. The N-terminal subdomain of one molecule interacts with C-terminal subdomain of the other molecule and vice versa. The two extended linkers cross over in the middle of each molecule and each contribute a β-strand to the antiparallel β-sheet in the C-terminal subdomain of the other molecule. The N-termini of the two monomers lie relatively close to each other, whereas the solvent-exposed C-termini are positioned on opposite sides of the molecule. Processing at the NS2/NS3 junction requires the NS3 serine protease domain and is stimulated by the addition of exogenous zinc. However, because NS2 contains a complete cysteine-protease active site with the C terminus positioned for catalysis, the function of NS3 remains undetermined .
The profile we developed covers the entire HCV NS2 protease domain.Last update:
November 2013 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|1||Authors||Pallaoro M. Lahm A. Biasiol G. Brunetti M. Nardella C. Orsatti L. Bonelli F. Orru S. Narjes F. Steinkuehler C.|
|Title||Characterization of the hepatitis C virus NS2/3 processing reaction by using a purified precursor protein.|
|Source||J. Virol. 75:9939-9946(2001).|
|2||Authors||Lorenz I.C. Marcotrigiano J. Dentzer T.G. Rice C.M.|
|Title||Structure of the catalytic domain of the hepatitis C virus NS2-3 protease.|