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 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Brass V,Berke JM,Montserret R,Blum HE,Penin F,Moradpour Ddoi
10.1073/pnas.0807298105subject
Has Abstractpub_date
2008-09-23 00:00:00pages
14545-50issue
38eissn
0027-8424issn
1091-6490pii
0807298105journal_volume
105pub_type
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