Table 3.

Summary of the properties of hepatitis C virus non-structural proteins

	NS2	NS3	NS4A	NS4B	NS5A	NS5B
Genome location	2769-3419	3420-5312	5313-5474	5475-6257	6258-7601	7602-9378
Translation processing site	Rough ER
Amino acid composition	810-1026	1027-1657	1658-1711	1712-1972	1973-2420	2421-3012
Molecular weight (kDa)	21-23	70	8	27	56-58	65-68
Cleavage	Viral cysteine protease NS2-3 and the serine-type protease activity of the viral NS3-NS4A complex
Crystal structure	C-terminal (aa904-1026) was solved	Revealed	Revealed	Not available	Revealed	Revealed
Functional unit	Homodimer	Monomer or oligomer	Monomer	Oligomer	Homodimer	Monomer
Common function	Replication module
Unique function	A metal-dependent proteinase, many functions dependent on the interaction with P7 and NS3. Participation in proteolytic cleavage at the NS2-NS3 junction of the polyprotein. Both the TMDs and protease domain of NS2 are required for the production of virus particles	The DAA targeting protein. NS3 was anchored in ER membrane by cofactor NS4A. NS3-4A complex has serine-type protease activity and NTPase/RNA helicase activities. Nonspecific cleavage of two critical interferon induction proteins: MAVS and TRIF	The central portion of NS4A, residues 21-32, intercalates into NS3 and activates the protease activity by stabilizing this protease subdomain and contributing to the substrate recognition site. The C-terminal acidic portion of NS4A interacts with the NS3 helicase and other HCV proteins and contributes to RNA replication as well as assembly	A master organizer of replication complex formation. NTPase activity? RNA binding?	Produced as multiple phospho-variants. RNA-binding phosphoprotein involved in RNA replication. Phosphorylation of a specific serine residue within the C-terminus by CKIIα is essential for virus assembly. The interaction of NS5A with the cLD-bound core protein is the key steps in HCV assembly	RNA-dependent RNA polymerase
Major scotomas	How HCV particles are organized? What is the accurate duty of each nonstructural protein in viral lifecycle? How do the nonstructural proteins utilize host cellular factors for its own survival? Why HCV lifecycle is tightly associated with components of LDLs and VLDLs?

Start co-ordinates based on H77 (accession number, NC_004102). Aa: Amino acid; TMD: Transmembrane domain; CKII: Casein kinase II; cLD: Cytoplasmic lipid droplet; LDL: Low-density lipoprotein; VLDL: Very-low-density lipoprotein; MAVS: Mitochondrial antiviral signaling protein; TRIF: TIR-domain-containing adaptor inducing interferon; HCV: Hepatitis C virus.