期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 38, 页码 14545-14550出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807298105
关键词
HCV; NMR; replication complex; serine protease; nonstructural protein
资金
- Swiss National Science Foundation [3100A0-107831/1]
- Swiss Cancer League [OCS-01762-08-2005]
- Leenaards Foundation
- Deutsche Forschungsgemeinschaft [Mo 799/1-3, Br 3440/2-1]
- Bundesministerium fur Bildung und Forschung [01 KI 9951]
- European Commission [LSHM-CT-2004-503359]
- French Centre National de la Recherche Scientifique
- Agence Nationale de Recherches sur le SIDA et les Hepatites Virales
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 a-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.
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