{PDOC51693} {PS51693; HCV_NS2_PRO} {BEGIN} ********************************************************************* * Hepacivirus nonstructural protein 2 (NS2) protease domain profile * ********************************************************************* 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 ). 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 alpha-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 beta-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 beta-strand to the antiparallel beta-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 [2]. The profile we developed covers the entire HCV NS2 protease domain. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: November 2013 / First entry. [ 1] Pallaoro M., Lahm A., Biasiol G., Brunetti M., Nardella C., Orsatti L., Bonelli F., Orru S., Narjes F., Steinkuehler C. "Characterization of the hepatitis C virus NS2/3 processing reaction by using a purified precursor protein." J. Virol. 75:9939-9946(2001). PubMed=11559826; DOI=10.1128/JVI.75.20.9939-9946.2001 [ 2] Lorenz I.C., Marcotrigiano J., Dentzer T.G., Rice C.M. "Structure of the catalytic domain of the hepatitis C virus NS2-3 protease." Nature 442:831-835(2006). PubMed=16862121; DOI=10.1038/nature04975 [E1] https://viralzone.expasy.org/37?outline=all_by_species [E2] https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=c18 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}