Protein kinase C recognizes the protein kinase A-binding motif of nonstructural protein 3 of hepatitis C virus
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Protein kinase C recognizes the protein kinase A-binding motif of nonstructural protein 3 of hepatitis C virus. / Borowski, P; Schulze zur Wiesch, J; Resch, K; Feucht, H; Laufs, R; Schmitz, H.
in: J BIOL CHEM, Jahrgang 274, Nr. 43, 22.10.1999, S. 30722-8.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Protein kinase C recognizes the protein kinase A-binding motif of nonstructural protein 3 of hepatitis C virus
AU - Borowski, P
AU - Schulze zur Wiesch, J
AU - Resch, K
AU - Feucht, H
AU - Laufs, R
AU - Schmitz, H
PY - 1999/10/22
Y1 - 1999/10/22
N2 - The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) inhibits the nuclear transport and the enzymatic activity of the catalytic subunit of protein kinase A. This inhibition is mediated by an arginine-rich domain localized between amino acids 1487-1500 of the HCV polyprotein. The data presented here indicate that the arginine-rich domain, when embedded in recombinant fragments of NS3, interacts with the catalytic site of protein kinase C (PKC) and inhibits the phosphorylation mediated by this enzyme in vitro and in vivo. Furthermore, a direct binding of PKC to the NS3 fragments leads to an inhibition of the free shuttling of the kinase between the cytoplasm and the particulate fraction. In contrast, a peptide corresponding to the arginine-rich domain (HCV (1487-1500)), despite also being a PKC inhibitor, did not influence the PKC shuttling process and was transported to the particulate fraction by the translocating kinase upon activation with tetradecanoylphorbol-13-acetate. Using the tetradecanoylphorbol-13-acetate -stimulated respiratory burst of NS3-introduced neutrophils as a model system, we could demonstrate that NS3 is able to block PKC-mediated functions within intact cells. Our data support the possibility that NS3 disrupts the PKC-mediated signal transduction.
AB - The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) inhibits the nuclear transport and the enzymatic activity of the catalytic subunit of protein kinase A. This inhibition is mediated by an arginine-rich domain localized between amino acids 1487-1500 of the HCV polyprotein. The data presented here indicate that the arginine-rich domain, when embedded in recombinant fragments of NS3, interacts with the catalytic site of protein kinase C (PKC) and inhibits the phosphorylation mediated by this enzyme in vitro and in vivo. Furthermore, a direct binding of PKC to the NS3 fragments leads to an inhibition of the free shuttling of the kinase between the cytoplasm and the particulate fraction. In contrast, a peptide corresponding to the arginine-rich domain (HCV (1487-1500)), despite also being a PKC inhibitor, did not influence the PKC shuttling process and was transported to the particulate fraction by the translocating kinase upon activation with tetradecanoylphorbol-13-acetate. Using the tetradecanoylphorbol-13-acetate -stimulated respiratory burst of NS3-introduced neutrophils as a model system, we could demonstrate that NS3 is able to block PKC-mediated functions within intact cells. Our data support the possibility that NS3 disrupts the PKC-mediated signal transduction.
KW - Amino Acid Sequence
KW - Animals
KW - Arginine
KW - Binding Sites
KW - Brain/enzymology
KW - Cloning, Molecular
KW - Cyclic AMP-Dependent Protein Kinases/metabolism
KW - Enzyme Activation
KW - Hepacivirus/metabolism
KW - Humans
KW - Kinetics
KW - Neutrophils/enzymology
KW - Peptide Fragments/chemistry
KW - Protein Kinase C/metabolism
KW - Rats
KW - Recombinant Proteins/chemistry
KW - Tetradecanoylphorbol Acetate/pharmacology
KW - Viral Nonstructural Proteins/chemistry
U2 - 10.1074/jbc.274.43.30722
DO - 10.1074/jbc.274.43.30722
M3 - SCORING: Journal article
C2 - 10521461
VL - 274
SP - 30722
EP - 30728
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 43
ER -