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Media type:
E-Article
Title:
Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex
Contributor:
Brass, Volker;
Berke, Jan Martin;
Montserret, Roland;
Blum, Hubert E.;
Penin, François;
Moradpour, Darius
Published:
Proceedings of the National Academy of Sciences, 2008
Published in:
Proceedings of the National Academy of Sciences, 105 (2008) 38, Seite 14545-14550
Language:
English
DOI:
10.1073/pnas.0807298105
ISSN:
1091-6490;
0027-8424
Origination:
Footnote:
Description:
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 α 0 , 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.