THE HEPATITIS-C VIRUS NS4A PROTEIN - INTERACTIONS WITH THE NS4B AND NS5A PROTEINS

Citation
C. Lin et al., THE HEPATITIS-C VIRUS NS4A PROTEIN - INTERACTIONS WITH THE NS4B AND NS5A PROTEINS, Journal of virology, 71(9), 1997, pp. 6465-6471
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Virology
Journal title
ISSN journal
0022-538X
Volume
71
Issue
9
Year of publication
1997
Pages
6465 - 6471
Database
ISI
SICI code
0022-538X(1997)71:9<6465:THVNP->2.0.ZU;2-B
Abstract
Hepatitis C virus encodes a large polyprotein precursor that is proteo lytically processed into at least 10 distinct products, in the order N H2C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH. A serine proteinase enc oded in the N-terminal 181 residues of the NS3 nonstructural protein i s responsible for cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5 B) in the nonstructural region. NS4A, a 54-residue nonstructural prote in which forms a stable complex with the NS3 proteinase, is required a s a cofactor for cleavage at the 3/4A and 4B/5A sites and enhances pro cessing at the 4A/4B end 5A/5B sites. Recently reported crystal struct ures demonstrated that NS4A forms an integral part of the NS3 serine p roteinase. In this report, we present evidence that NS4A forms a nonio nic detergent-stable complex with the NS4B5A polyprotein substrate, wh ich may explain the requirement of NS4A for the 4B/5A cleavage. Isoleu cine-29 of NS4A, which has been previously shown to be essential for i ts proteinase cofactor activity and formation of the NS3 complex was f ound to be important for the interaction between NS4A and the NS4B5A s ubstrate. In addition, two more hydrophobic residues in the NS4A centr al region (valine-23 and isoleucine-25) were also shown to be essentia l for the cofactor activity and for the interaction with either the NS 3 proteinase or the NS4B5A polyprotein substrate. Finally, the possibl e mechanisms by which these viral proteins interact with each other ar e discussed.