Internal cleavages of hepatitis C virus NS3 induced by P1 mutations at the NS3/4A cleavage site.
Despite being the focus of intensive investigation for its enzymatic activities and its roles in HCV virus replication, little is known about the internal processing of NS3. Here we show that single mutations at P1 position of the NS3/4A junction lead to alternative cleavages. Among the multiple novel cleavage products observed, there were two predominant species of about 12 kDa (p12) and 67 kDa (p67). This p12 species consists of the NS4A and about a 6 kDa long C-terminal region of NS3 and forms a complex with NS3. The remaining NS3 corresponds to the p67 species. This alternative cleavage is an NS3 protease-mediated intra-molecular event and more interestingly can also be induced with low concentrations of one NS3 protease inhibitor examined. Our results led us to propose a model explaining the alternative cleavage observed and its functional role.
Hou
Xiaohong
X
Antiviral Drug Discovery, Achillion Pharmaceuticals, Inc., New Haven, CT 06511, USA.
Yang
Wengang
W
Zhao
Yongsen
Y
Agarwal
Atul
A
Huang
Mingjun
M
D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D020125:Mutation, Missense; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus