Article: article from journal or magazin.
Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex.
Proceedings of the National Academy of Sciences of the United States of America
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
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 alpha-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 alpha(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.
Amino Acid Sequence, Carrier Proteins, DNA Mutational Analysis, Hepacivirus, Models, Molecular, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Viral Matrix Proteins, Viral Nonstructural Proteins, Viral Proteins
Web of science
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