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arterivirus replicase ORF1a + H2O
?
arterivirus replicase ORF1a protein + H2O
?
arterivirus replicase ORF1ab + H2O
?
arterivirus replicase ORF1b + H2O
?
Dabsyl-Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu-Gly-Arg-His-Phe-Glu-EDANS + H2O
Dabsyl-Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu + Gly-Arg-His-Phe-Glu-EDANS
-
-
-
?
Lys-Asp-Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu-Gly-Arg-His-Phe-Thr-Trp + H2O
Lys-Asp-Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu + Gly-Arg-His-Phe-Thr-Trp
-
-
-
?
Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu-Gly-Arg-His-Phe-Thr-Trp-Tyr-Gln + H2O
Lys-Thr-Ala-Tyr-Phe-Gln-Leu-Glu + Gly-Arg-His-Phe-Thr-Trp-Tyr-Gln
-
-
-
?
NF-kappaB essential modulator NEMO + H2O
?
NSP3'4 protein + H2O
?
recombinantly expressed substrate NSP3'4 covering the last 8 residues of nonstructural protein 3 and the whole amino acid sequence of nonstructural protein 4 mutant S118A
-
-
?
proform caspase-3 + H2O
mature caspase-3 + ?
activation
-
-
?
proform caspase-8 + H2O
mature caspase-8 + ?
activation
-
-
?
proform caspase-9 + H2O
mature caspase-9 + ?
activation
-
-
?
additional information
?
-
arterivirus replicase ORF1a + H2O
?
-
cleavage sites are Glu1430/Gly and Glu1452/Ser
-
?
arterivirus replicase ORF1a + H2O
?
-
ORF1a can be cleaved following two alternative pathways. In the majority nsp3-8 precursors are cleaved at the nsp4/5 site yielding nsp3-4 and nsp5-8. The latter product is then cleaved at nsp7/8 only. In the alternative proteolytic cascade the nsp4/5 site remains uncleaved while the nsp5/6 and nsp6/7 sites are processed. nsp3-8 has to interact with cleaved nsp2 to allow processing of the nsp4/5 junction, when nsp2 cofactor is absent the alternative pathway is used
-
?
arterivirus replicase ORF1a protein + H2O
?
-
-
?
arterivirus replicase ORF1a protein + H2O
?
nsp4 and an unidentified protease is responsible for the cleavage sites nsp2/3, nsp3/4, nsp4/5 and nsp5/6 in the ORF1a protein
-
?
arterivirus replicase ORF1a protein + H2O
?
-
-
?
arterivirus replicase ORF1ab + H2O
?
-
cleavage sites are the junctions at nsp3/4, Nsp4/5, 2 internal nsp5 sites, nsp5/6, p80/p50, p50/p26, p26/p12, enzyme cleaves between Glu and Gly, Glu and Ser or Glu and Lys
-
?
arterivirus replicase ORF1ab + H2O
?
-
cleavage sites are the junctions at nsp3/4, Nsp4/5, 2 internal nsp5 sites, nsp5/6, p80/p50, p50/p26, p26/p12, enzyme cleaves between Glu and Gly, Glu and Ser or Glu and Lys
-
?
arterivirus replicase ORF1b + H2O
?
-
protein is processed by nsp4 serine protease
-
?
arterivirus replicase ORF1b + H2O
?
-
protein is processed by nsp4 serine protease at the following sites: nsp9/10 i.e. p80/p50, cleavage occurs between Glu2370 and Ser, nsp10/11 i.e. p50/p26, cleavage occurs between Gln2837 and Ser, nsp11/12 i.e. nsp26/p12, cleavage between Glu3056 and Gly
-
?
arterivirus replicase ORF1b + H2O
?
-
protein is processed by nsp4 serine protease
-
?
NF-kappaB essential modulator NEMO + H2O
?
-
-
-
-
?
NF-kappaB essential modulator NEMO + H2O
?
-
-
-
?
additional information
?
-
nsp4 cleaves multiple GluX(Gly/Ser/Ala) sites, X: cleavage site
-
?
additional information
?
-
-
nsp4 cleaves multiple GluX(Gly/Ser/Ala) sites, X: cleavage site
-
?
additional information
?
-
-
protease has a specificity for Glu/Gly or Glu/Ser substrates
-
?
additional information
?
-
-
enzyme is the main viral protease
-
?
additional information
?
-
-
the enzyme controls the maturation of the replicase complex. The C-terminal domain has a modulating role in nsp4-mediated autoprocessing of the arterivirus replicase polyproteins
-
-
?
additional information
?
-
-
the enzyme cleaves the cognate nsp6/7- and nsp7/8 site in in vitro synthesized substrates
-
-
?
additional information
?
-
nsp4 cleaves multiple GluX(Gly/Ser/Ala) sites, X: cleavage site
-
?
additional information
?
-
the enzyme shows a 3C-like serine protease activity
-
-
?
additional information
?
-
-
the enzyme shows a 3C-like serine protease activity
-
-
?
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Arteritis
Mutagenesis Analysis of the nsp4 Main Proteinase Reveals Determinants of Arterivirus Replicase Polyprotein Autoprocessing.
Breast Neoplasms
HCV nonstructural protein 4 is associated with aggressiveness features of breast cancer.
Bronchitis
Infectious Bronchitis Virus Nonstructural Protein 4 Alone Induces Membrane Pairing.
Communicable Diseases
Prediction of promiscuous T cell epitopes in RNA dependent RNA polymerase of Chikungunya virus.
Encephalomyelitis, Venezuelan Equine
Nucleotide sequences of the 26S mRNAs of the viruses defining the Venezuelan equine encephalitis antigenic complex.
Gastroenteritis
Rotavirus nonstructural protein NSP4 induces heterotypic antibody responses during natural infection in children.
Gastroenteritis
[Role of rotavirus non-structural protein 4 in causing of acute gastroenteritis]
Hepatitis
Crystal structure of the C-terminal cytoplasmic domain of non-structural protein 4 from mouse hepatitis virus A59.
Hepatitis
Murine Hepatitis Virus Nonstructural Protein 4 Regulates Virus-induced Membrane Modifications and Replication Complex Function.
Hepatitis C
Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes.
Hepatitis C
Immunohistostaining of hepatitis C virus non-structural protein 4 in ependymocytes of uninfected mice: an antigenic mimicry?
Hepatitis C
Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.
Hypersensitivity
Prediction of promiscuous T cell epitopes in RNA dependent RNA polymerase of Chikungunya virus.
Infections
Epitope mapping and use of epitope-specific antisera to characterize the VP5* binding site in rotavirus SA11 NSP4.
Infections
Expression of Concern: Rotaviral enterotoxin nonstructural protein 4 targets mitochondria for activation of apoptosis during infection.
Infections
Rotaviral enterotoxin nonstructural protein 4 targets mitochondria for activation of apoptosis during infection.
Infections
Rotaviral nonstructural protein 4 triggers dynamin-related protein 1-dependent mitochondrial fragmentation during infection.
Infections
Tyrosine phosphorylation modulates mitochondrial chaperonin Hsp60 and delays rotavirus NSP4-mediated apoptotic signaling in host cells.
Infections
Withdrawal: Rotaviral enterotoxin nonstructural protein 4 targets mitochondria for activation of apoptosis during infection.
Neoplasms
The effect of bovine rotavirus and its nonstructural protein 4 on ER stress-mediated apoptosis in HeLa and HT-29 cells.
Porcine Reproductive and Respiratory Syndrome
Characterization of the biochemical properties and identification of amino acids forming the catalytic center of 3C-like proteinase of porcine reproductive and respiratory syndrome virus.
Porcine Reproductive and Respiratory Syndrome
Induction of Apoptosis by the Nonstructural Protein 4 and 10 of Porcine Reproductive and Respiratory Syndrome Virus.
Porcine Reproductive and Respiratory Syndrome
Intracellularly expressed nanobodies against non-structural protein 4 of porcine reproductive and respiratory syndrome virus inhibit virus replication.
Porcine Reproductive and Respiratory Syndrome
Nonstructural Protein 4 of Porcine Reproductive and Respiratory Syndrome Virus Modulates Cell Surface Swine Leukocyte Antigen Class I Expression by Downregulating ?2-Microglobulin Transcription.
Porcine Reproductive and Respiratory Syndrome
Porcine reproductive and respiratory syndrome virus nonstructural protein 4 antagonizes beta interferon expression by targeting the NF-?B essential modulator.
Porcine Reproductive and Respiratory Syndrome
Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 4 Cleaves Porcine DCP1a To Attenuate Its Antiviral Activity.
Porcine Reproductive and Respiratory Syndrome
Porcine reproductive and respiratory syndrome virus nonstructural protein 4 induces apoptosis dependent on its 3C-like serine protease activity.
Porcine Reproductive and Respiratory Syndrome
Serodiagnosis, targeting nonstructural protein 4, of porcine reproductive and respiratory syndrome virus.
Porcine Reproductive and Respiratory Syndrome
The amino acid at residue 155 in nonstructural protein 4 of porcine reproductive and respiratory syndrome virus contributes to its inhibitory effect for interferon-? transcription in vitro.
Rotavirus Infections
Rotavirus enterotoxin NSP4 binds to the extracellular matrix proteins laminin-beta3 and fibronectin.
Rotavirus Infections
Silencing of the Rotavirus NSP4 Protein Decreases the Incidence of Biliary Atresia in Murine Model.
Seizures
NSP4 antibody levels in rotavirus gastroenteritis patients with seizures.
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malfunction
the ability of nsp4 to induce apoptosis is significantly impaired by His39, Asp64, and Ser118 mutations
physiological function
porcine reproductive and respiratory syndrome virus nonstructural protein 4 is a critical apoptosis inducer dependent on its serine protease activity, the full-length of nsp4 structure is required for its apoptosis-inducing activity, the enzyme can induce apoptosis in diverse cell lines, e.g. in HeLa cells, overview
physiological function
-
nsp4 inhibits virus-induced IFN-beta production by targeting NF-kappaB essential modulator NEMO for proteolytic cleavage. The scission occurs at sites E166, E171, Q205, and E349
physiological function
nsp4 inhibits virus-induced IFN-beta production by targeting NF-kappaB essential modulator NEMO for proteolytic cleavage. The scission occurs at sites E166, E171, Q205, and E349. NEMO cleavage at E349 alone may not be sufficient to completely inactivate the interferon response via this signaling adaptor
additional information
residues His39, Asp64, and Ser118 are essential for the enzyme to trigger apoptosis
additional information
-
residues His39, Asp64, and Ser118 are essential for the enzyme to trigger apoptosis
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D1129E
mutant is able to cleave the Nsp4/5 site with wild-type efficiently but does not process the Nsp3/4 and Nsp5/6 junctions
D1129K
no Nsp3456 cleavage
D1129V
no Nsp3456 cleavage
H1103G
complete inhibition of Nsp3456 processing
H1103R
complete inhibition of Nsp3456 processing
H1198L
completely abolished processing of Nsp4/5 and Nsp5/6
H1198R
completely abolished processing of Nsp4/5 and Nsp5/6
H1198Y
completely abolished processing of Nsp4/5 and Nsp5/6
S1184C
mutation has no effect on Nsp3456 processing
S1184F
mutation has no effect on Nsp3456 processing
S1184Y
mutation has no effect on Nsp3456 processing
T1179D
completely abolished processing of Nsp4/5 and Nsp5/6
T1179G
reduced cleavage of Nsp4/5, no cleavage of Nsp5/6 site
T1179N
retains wild-type activity towards Nsp4/5, cleaves Nsp5/6 with increased efficiency
T1179S
reduced cleavage of Nsp4/5, no cleavage of Nsp5/6 site
H1103G
-
complete inhibition of Nsp3456 processing
-
H1103R
-
complete inhibition of Nsp3456 processing
-
S1184C
-
mutation has no effect on Nsp3456 processing
-
S1184F
-
mutation has no effect on Nsp3456 processing
-
S1184I
-
mutation has no effect on Nsp3456 processing
-
D64A
site-directed mutagenesis, the mutant shows significantly reduced ability to induce apoptosis compared to the wild-type enzyme
H39A
site-directed mutagenesis, the mutant shows significantly reduced ability to induce apoptosis compared to the wild-type enzyme
S1184I
mutation has no effect on Nsp3456 processing
S1184I
-
no cleavage between nsp9 and nsp10
S118A
catalytic residue, mutant protein inactive
S118A
site-directed mutagenesis, the mutant shows significantly reduced ability to induce apoptosis compared to the wild-type enzyme
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Snijder, E.J.; Wassenaar, A.L.; Spaan, W.J.
Proteolytic processing of the N-terminal region of the equine arteritis virus replicase
Adv. Exp. Med. Biol.
342
227-232
1993
equine arteritis virus (P19811)
brenda
Snijder, E.J.; Wassenaar, A.L.; van Dinten, L.C.; Spaan, W.J.; Gorbalenya, A.E.
The arterivirus nsp4 protease is the prototype of a novel group of chymotrypsin-like enzymes, the 3C-like serine proteases
J. Biol. Chem.
271
4864-4871
1996
equine arteritis virus (P19811), equine arteritis virus, equine arteritis virus Bucyrus (P19811)
brenda
Barrette-Ng, I.H.; Ng, K.K.; Mark, B.L.; Van Aken, D.; Cherney, M.M.; Garen, C.; Kolodenko, Y.; Gorbalenya, A.E.; Snijder, E.J.; James, M.N.
Structure of arterivirus nsp4. The smallest chymotrypsin-like proteinase with an alpha/beta C-terminal extension and alternate conformations of the oxyanion hole
J. Biol. Chem.
277
39960-39966
2002
equine arteritis virus (P19811), equine arteritis virus
brenda
den Boon, J.A.; Snijder, E.J.; Chirnside, E.D.; de Vries, A.A.; Horzinek, M.C.; Spaan, W.J.
Equine arteritis virus is not a togavirus but belongs to the coronaviruslike superfamily
J. Virol.
65
2910-2920
1991
equine arteritis virus (P19811)
brenda
van Dinten, L.C.; Wassenaar, A.L.; Gorbalenya, A.E.; Spaan, W.J.; Snijder, E.J.
Processing of the equine arteritis virus replicase ORF1b protein: identification of cleavage products containing the putative viral polymerase and helicase domains
J. Virol.
70
6625-6633
1996
equine arteritis virus, equine arteritis virus Bucyrus
brenda
Wassenaar, A.L.; Spaan, W.J.; Gorbalenya, A.E.; Snijder, E.J.
Alternative proteolytic processing of the arterivirus replicase ORF1a polyprotein: evidence that NSP2 acts as a cofactor for the NSP4 serine protease
J. Virol.
71
9313-9322
1997
equine arteritis virus
brenda
van Dinten, L.C.; Rensen, S.; Gorbalenya, A.E.; Snijder, E.J.
Proteolytic processing of the open reading frame 1b-encoded part of arterivirus replicase is mediated by nsp4 serine protease and Is essential for virus replication
J. Virol.
73
2027-2037
1999
equine arteritis virus
brenda
van Aken, D.; Snijder, E.J.; Gorbalenya, A.E.
Mutagenesis analysis of the nsp4 main proteinase reveals determinants of arterivirus replicase polyprotein autoprocessing
J. Virol.
80
3428-3437
2006
equine arteritis virus
brenda
van Aken, D.; Benckhuijsen, W.E.; Drijfhout, J.W.; Wassenaar, A.L.; Gorbalenya, A.E.; Snijder, E.J.
Expression, purification, and in vitro activity of an arterivirus main proteinase
Virus Res.
120
97-106
2006
equine arteritis virus
brenda
Tian, X.; Lu, G.; Gao, F.; Peng, H.; Feng, Y.; Ma, G.; Bartlam, M.; Tian, K.; Yan, J.; Hilgenfeld, R.; Gao, G.F.
Structure and cleavage specificity of the chymotrypsin-like serine protease (3CLSP/nsp4) of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)
J. Mol. Biol.
392
977-993
2009
porcine reproductive and respiratory syndrome virus (A1E8J1), porcine reproductive and respiratory syndrome virus
brenda
Ma, Z.; Wang, Y.; Zhao, H.; Xu, A.T.; Wang, Y.; Tang, J.; Feng, W.H.
Porcine reproductive and respiratory syndrome virus nonstructural protein 4 induces apoptosis dependent on its 3C-like serine protease activity
PLoS ONE
8
e69387
2013
porcine reproductive and respiratory syndrome virus (Q91F54), porcine reproductive and respiratory syndrome virus
brenda
Chen, J.; Wang, D.; Sun, Z.; Gao, L.; Zhu, X.; Guo, J.; Xu, S.; Fang, L.; Li, K.; Xiaoa, S.
Arterivirus nsp4 antagonizes interferon beta production by proteolytically cleaving NEMO at multiple sites
J. Virol.
93
e00385
2019
equine arteritis virus, porcine reproductive and respiratory syndrome virus (E3V2B5)
brenda