PROSITE documentation PDOC51822
Hepacivirus/Pegivirus NS3 protease domain profile


Hepaciviruses [E1] and pegiviruses [E2] are two genera of the viral family Flaviviridae [E3]. Both the Hepacivirus and Pegivirus genera contain species that infect humans. Hepatitis C is a disease caused by the hepatitis C virus (HCV), a hepacivirus that is one of the most important causes of severe chronic liver disease. Human pegivirus (HPgV) is the most closely related human virus to HCV. HPgV is a lymphotropic virus but unlike HCV it has little, if any, associated pathogenicity in humans. The genome structures of hepaciviruses and pegiviruses are conserved and share many similarities. Both genera are single-stranded positive sense RNA viruses and their genomes encode large polyproteins, which are cleaved into structural and nonstructural (NS) proteins through the action of cellular peptidases as well as the viral-encoded proteases including NS3/4A. NS3 contains Ser protease and RNA helicase activities that require its cofactor NS4A. The NS3 protease domain resides in the N-terminal one third of the NS3 protein whereas the C-terminal two-third contain a helicase (see <PDOC51192>). The NS3/A4 protease is not only essential for generating mature viral proteins required for viral replication, but also hydrolyzes proteins, which are part of the innate immune system, thereby confounding the innate immune response to viral infection [1,2,3,4,5]. The Hepacivirus/Pegivirus NS3 protease domain forms the peptidase family S29 (hepacivirin family) of clan PA [E4].

The Hepacivirus/Pegivirus NS3 protease domain folds as a trypsin-like proteinase with two six-stranded β barrels and a catalytic triad of His, Asp, Ser (see <PDB:1A1Q>). It exhibits some features that are highly unusual for a trypsin-like proteinase: it is covalently attached to a helicase possessing NTPase activity, it requires a protein cofactor (NS4A), and displays sensitivity to metal ions [1].

The profile we developed covers the entire Hepacivirus/Pegivirus NS3 protease domain.

Last update:

November 2016 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

HV_PV_NS3_PRO, PS51822; Hepacivirus/Pegivirus NS3 protease domain profile  (MATRIX)


1AuthorsLove R.A. Parge H.E. Wickersham J.A. Hostomsky Z. Habuka N. Moomaw E.W. Adachi T. Hostomska Z.
TitleThe crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site.
SourceCell 87:331-342(1996).
PubMed ID8861916

2AuthorsLi X.-D. Sun L. Seth R.B. Pineda G. Chen Z.J.
TitleHepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.
SourceProc. Natl. Acad. Sci. U.S.A. 102:17717-17722(2005).
PubMed ID16301520

3AuthorsRomano K.P. Ali A. Aydin C. Soumana D. Oezen A. Deveau L.M. Silver C. Cao H. Newton A. Petropoulos C.J. Huang W. Schiffer C.A.
TitleThe molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.
SourcePLoS Pathog. 8:E1002832-E1002832(2012).
PubMed ID22910833

4AuthorsTheze J. Lowes S. Parker J. Pybus O.G.
TitleEvolutionary and Phylogenetic Analysis of the Hepaciviruses and Pegiviruses.
SourceGenome Biol. Evol. 7:2996-3008(2015).
PubMed ID26494702

5AuthorsAnggakusuma Brown R.J.P. Banda D.H. Todt D. Vieyres G. Steinmann E. Pietschmann T.
TitleHepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission.
SourceJ. Virol. 90:10670-10681(2016).
PubMed ID27654291





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