Hepatitis C virus replicase NS5A
Hepatitis C virus(HCV)
Hepatitis C is a liver disease caused by the Hepatitis C virus (HCV). Infection by HCV results in clinical hepatitis and is often followed by the virus establishing a chronic infection in the liver. Such an infection results in recurring liver inflammation which may progress to cirrhosis and liver cancer (hepatocellular carcinoma). HCVs infect about 3% of the global population and broadly effective treatments are available.The HCV genome has a single open reading frame that encodes a precursor protein consisting of several different proteins connected together in succession, called a polyprotein. The polyprotein is divided into structural and nonstructural (NS) proteins. The structural proteins form the envelope and the core components of HCV. The NS proteins are responsible for the catalytic machinery for the HCV genome replication. The protein NS5A is a component of the HCV replicase, which in turn is part of the membrane associated multi-subunit HCV RNA replication machinery. NS5A also plays a role in regulating replication and modulates various cellular processes, including innate immunity and cell growth.
The NS5A has an amphipathic alpha-helix at its amino terminus through which it binds to the membrane. This is followed by domains I, II and III starting from the amino terminus. The structure shown here is that of domain I of NS5A. The structure shows two monomers, with each monomer having a single zinc binding site at its N-terminus formed by four cysteines. Mutations in the zinc-binding motif are lethal to HVC RNA replication, making domain I a putative drug target. The structure has an extensive amount of random coil near the N- and C- termini. It also has a single disulfide bond at the C-terminus. The dimeric form of the domain presents a basic groove which may act as the RNA binding pocket. However, it has not been established whether the domain dimerizes when present as a part of the whole NS5A in the HCV replicase.
Protein Data Bank (PDB)
Tellinghuisen, T.L. Marcotrigiano, J. Rice, C.M.; "Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase"; Nature; (2005) 435:374-379. PubMed:15902263
Author: Ashwini Patil