Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis - PubMed (original) (raw)

Fig 4. Required features of the p7-NS2-3-4A or NS2A-2B-3 polyprotein regions

The multifunctional enzyme NS3 and its hydrophobic neighbours in the polyprotein are emerging as conserved requirements for Flaviviridae progeny virion production. The determinants of this region involved in proteolysis, RNA replication, and infectious virus production are shown. Pro, protease; Hel/NTP, helicase/nucleoside triphosphatase; yellow, hydrophobic sequences involved in membrane association; orange, zinc-coordination motifs. Green, required region; blue, implicated through adaptive mutations; dark grey, of unknown importance; white circle, enzymatic activity required; black circle, enzymatic activity not required; grey circle, enzymatic activity of unknown importance; black arrow head, site of processing by indicated catalytic activity; white arrow head, cryptic site of processing by indicated catalytic activity. NS2-mediated autoproteolysis of its carboxy terminus from NS3 is an essential step in hepacivirus and pestivirus polyprotein processing. The protease domain of NS3 is required for the catalytic activity of HCV NS2; the involvement of the zinc-binding site, but not the enzymatic activity, of NS3 suggests a structural contribution,,. Pestivirus NS2 protease activity requires only two residues of NS3,, but depends on the entire NS2 membrane-associated domain and on a cellular cofactor, Jiv,. NS3 protease activity is present in the amino-terminal domains of the hepacivirus, pestivirus, and flavivirus proteins; NS3 also possesses helicase/NTPase activity. HCV and pestivirus NS4A and flavivirus NS2B proteins are essential cofactors for NS3-mediated proteolysis. Replication requires the protease and helicase/NTPase functions of NS3. HCV and pestivirus NS2 proteins are not involved in RNA accumulation after release of NS3,,; flavivirus NS2A and NS2B are essential. Infectious virus production by HCV and pestivirus genomes requires the p7 protein,,. HCV morphogenesis also depends on a function of NS2 that is independent of its protease activity, and a role for NS3 has been suggested by emergent mutations,. Infectious pestivirus production requires the uncleaved NS2-3 precursor protein in conjunction with NS4A, again without a requirement for the known enzymatic activities of NS2 or NS3,. Flavivirus morphogenesis requires NS2A, likely in cooperation with NS3,,; in a second, proteolytic role, NS3 and its cofactor NS2B are important for capsid protein processing,,.