Biomaterial Database

A central region in the hepatitis C virus NS4A protein allows formation of an active NS3-NS4A serine proteinase complex in vivo and in vitro. 1995

C Lin, and J A Thomson, and C M Rice

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.

A virus-encoded serine proteinase mediates four site-specific cleavages in the hepatitis C virus polyprotein. In addition to the catalytic domain, which is located in the N-terminal one-third of nonstructural protein NS3, the 54-residue NS4A protein is required for cleavage at some but not all sites. Here, we provide evidence for a non-ionic detergent-stable interaction between NS4A and the NS3 serine proteinase domain and demonstrate that the central region of NS4A plays a key role in NS4A-dependent processing. Hydrophobic residues, in particular Ile-29, were shown to be important for NS4A activity, and a synthetic peptide, spanning NS4A residues 22 to 34, could substitute for intact NS4A in a cell-free trans cleavage assay. Furthermore, NS4A mutations, which abolished or inhibited processing, correlated with destabilization of the NS3-NS4A complex. These results suggest that a stable interaction exists between the central region of NS4A and the NS3 catalytic domain which is required for NS4A-dependent processing. Since NS4A is required for processing at certain serine proteinase-dependent cleavage sites, this interaction may represent a new target for development of antiviral compounds.

UI	MeSH Term	Description	Entries
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D000595	Amino Acid Sequence	The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.	Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D012697	Serine Endopeptidases	Any member of the group of ENDOPEPTIDASES containing at the active site a serine residue involved in catalysis.	Serine Endopeptidase,Endopeptidase, Serine,Endopeptidases, Serine
D017361	Viral Nonstructural Proteins	Proteins encoded by a VIRAL GENOME that are not structural components of VIRUS PARTICLES. Some of these proteins may play roles within the infected cell during VIRUS REPLICATION or act in regulation of virus replication or VIRUS ASSEMBLY.	Nonstructural Proteins, Viral,NS Proteins, Viral,Viral NS Proteins,Viral Non-Structural Proteins,Viral Nonstructural Protein,Viral Nonstructural Proteins NS1,Viral Nonstructural Proteins NS2,Nonstructural Protein, Viral,Viral Non Structural Proteins
D017830	Octoxynol	Nonionic surfactant mixtures varying in the number of repeating ethoxy (oxy-1,2-ethanediyl) groups. They are used as detergents, emulsifiers, wetting agents, defoaming agents, etc. Octoxynol-9, the compound with 9 repeating ethoxy groups, is a spermatocide.	Octylphenoxypolyethoxyethanols,Octoxinol,Octoxinols,Octoxynol-9,Octoxynols,Octylphenoxy Polyethoxyethanol,Triton X-100,Triton X-305,Triton X-45,Octoxynol 9,Polyethoxyethanol, Octylphenoxy,Triton X 100,Triton X 305,Triton X 45,Triton X100,Triton X305,Triton X45