This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, C. Articles by Su, M. S. Search for Related Content PubMed PubMed Citation Articles by Lin, C. Articles by Su, M. S.

 Previous Article  |  Next Article 

J. Virol., Sep 1997, 6465-6471, Vol 71, No. 9
Copyright © 1997, American Society for Microbiology

The hepatitis C virus NS4A protein: interactions with the NS4B and NS5A proteins

C Lin, JW Wu, K Hsiao and MS Su
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139- 4242, USA. Lin@vpharm.com

Hepatitis C virus encodes a large polyprotein precursor that is proteolytically processed into at least 10 distinct products, in the order NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B -COOH. A serine proteinase encoded in the N-terminal 181 residues of the NS3 nonstructural protein is responsible for cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the nonstructural region. NS4A, a 54- residue nonstructural protein which forms a stable complex with the NS3 proteinase, is required as a cofactor for cleavage at the 3/4A and 4B/5A sites and enhances processing at the 4A/4B and 5A/5B sites. Recently reported crystal structures demonstrated that NS4A forms an integral part of the NS3 serine proteinase. In this report, we present evidence that NS4A forms a nonionic-detergent-stable complex with the NS4B5A polyprotein substrate, which may explain the requirement of NS4A for the 4B/5A cleavage. Isoleucine-29 of NS4A, which has been previously shown to be essential for its proteinase cofactor activity and formation of the NS3 complex, was found to be important for the interaction between NS4A and the NS4B5A substrate. In addition, two more hydrophobic residues in the NS4A central region (valine-23 and isoleucine-25) were also shown to be essential for the cofactor activity and for the interaction with either the NS3 proteinase or the NS4B5A polyprotein substrate. Finally, the possible mechanisms by which these viral proteins interact with each other are discussed.

This article has been cited by other articles:

• Lindenbach, B. D., Pragai, B. M., Montserret, R., Beran, R. K. F., Pyle, A. M., Penin, F., Rice, C. M. (2007). The C Terminus of Hepatitis C Virus NS4A Encodes an Electrostatic Switch That Regulates NS5A Hyperphosphorylation and Viral Replication. J. Virol. 81: 8905-8918 [Abstract] [Full Text]  
• Blight, K. J. (2007). Allelic Variation in the Hepatitis C Virus NS4B Protein Dramatically Influences RNA Replication. J. Virol. 81: 5724-5736 [Abstract] [Full Text]  
• Graziani, R., Paonessa, G. (2004). Dominant negative effect of wild-type NS5A on NS5A-adapted subgenomic hepatitis C virus RNA replicon. J. Gen. Virol. 85: 1867-1875 [Abstract] [Full Text]  
• Ma, Y., Shimakami, T., Luo, H., Hayashi, N., Murakami, S. (2004). Mutational Analysis of Hepatitis C Virus NS5B in the Subgenomic Replicon Cell Culture. J. Biol. Chem. 279: 25474-25482 [Abstract] [Full Text]  
• Scholle, F., Li, K., Bodola, F., Ikeda, M., Luxon, B. A., Lemon, S. M. (2004). Virus-Host Cell Interactions during Hepatitis C Virus RNA Replication: Impact of Polyprotein Expression on the Cellular Transcriptome and Cell Cycle Association with Viral RNA Synthesis. J. Virol. 78: 1513-1524 [Abstract] [Full Text]  
• El-Hage, N., Luo, G. (2003). Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. J. Gen. Virol. 84: 2761-2769 [Abstract] [Full Text]  
• Dimitrova, M., Imbert, I., Kieny, M. P., Schuster, C. (2003). Protein-Protein Interactions between Hepatitis C Virus Nonstructural Proteins. J. Virol. 77: 5401-5414 [Abstract] [Full Text]  
• Lundin, M., Monne, M., Widell, A., von Heijne, G., Persson, M. A. A. (2003). Topology of the Membrane-Associated Hepatitis C Virus Protein NS4B. J. Virol. 77: 5428-5438 [Abstract] [Full Text]  
• Piccininni, S., Varaklioti, A., Nardelli, M., Dave, B., Raney, K. D., McCarthy, J. E. G. (2002). Modulation of the Hepatitis C Virus RNA-dependent RNA Polymerase Activity by the Non-Structural (NS) 3 Helicase and the NS4B Membrane Protein. J. Biol. Chem. 277: 45670-45679 [Abstract] [Full Text]  
• Shirota, Y., Luo, H., Qin, W., Kaneko, S., Yamashita, T., Kobayashi, K., Murakami, S. (2002). Hepatitis C Virus (HCV) NS5A Binds RNA-dependent RNA Polymerase (RdRP) NS5B and Modulates RNA-dependent RNA Polymerase Activity. J. Biol. Chem. 277: 11149-11155 [Abstract] [Full Text]  
• Brass, V., Bieck, E., Montserret, R., Wolk, B., Hellings, J. A., Blum, H. E., Penin, F., Moradpour, D. (2002). An Amino-terminal Amphipathic alpha -Helix Mediates Membrane Association of the Hepatitis C Virus Nonstructural Protein 5A. J. Biol. Chem. 277: 8130-8139 [Abstract] [Full Text]  
• Schmidt-Mende, J., Bieck, E., Hugle, T., Penin, F., Rice, C. M., Blum, H. E., Moradpour, D. (2001). Determinants for Membrane Association of the Hepatitis C Virus RNA-dependent RNA Polymerase. J. Biol. Chem. 276: 44052-44063 [Abstract] [Full Text]  
• Khu, Y.-L., Koh, E., Lim, S. P., Tan, Y. H., Brenner, S., Lim, S. G., Hong, W. J., Goh, P.-Y. (2001). Mutations That Affect Dimer Formation and Helicase Activity of the Hepatitis C Virus Helicase. J. Virol. 75: 205-214 [Abstract] [Full Text]  
• Bartenschlager, R., Lohmann, V. (2000). Replication of hepatitis C virus. J. Gen. Virol. 81: 1631-1648 [Full Text]  
• Wölk, B., Sansonno, D., Kräusslich, H.-G., Dammacco, F., Rice, C. M., Blum, H. E., Moradpour, D. (2000). Subcellular Localization, Stability, and trans-Cleavage Competence of the Hepatitis C Virus NS3-NS4A Complex Expressed in Tetracycline-Regulated Cell Lines. J. Virol. 74: 2293-2304 [Abstract] [Full Text]  
• Neddermann, P., Clementi, A., De Francesco, R. (1999). Hyperphosphorylation of the Hepatitis C Virus NS5A Protein Requires an Active NS3 Protease, NS4A, NS4B, and NS5A Encoded on the Same Polyprotein. J. Virol. 73: 9984-9991 [Abstract] [Full Text]  
• Oliver Koch, J., Bartenschlager, R. (1999). Modulation of Hepatitis C Virus NS5A Hyperphosphorylation by Nonstructural Proteins NS3, NS4A, and NS4B. J. Virol. 73: 7138-7146 [Abstract] [Full Text]  
• Song, J, Fujii, M, Wang, F, Itoh, M, Hotta, H (1999). The NS5A protein of hepatitis C virus partially inhibits the antiviral activity of interferon. J. Gen. Virol. 80: 879-886 [Abstract]  
• Filocamo, G., Pacini, L., Nardi, C., Bartholomew, L., Scaturro, M., Delmastro, P., Tramontano, A., De Francesco, R., Migliaccio, G. (1999). Selection of Functional Variants of the NS3-NS4A Protease of Hepatitis C Virus by Using Chimeric Sindbis Viruses. J. Virol. 73: 561-575 [Abstract] [Full Text]