Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex
Abstract
Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane α-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix α0, formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- September 2008
- DOI:
- 10.1073/pnas.0807298105
- Bibcode:
- 2008PNAS..10514545B
- Keywords:
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- HCV;
- NMR;
- replication complex;
- serine protease;
- nonstructural protein;
- Biological Sciences:Medical Sciences