Characterisation of non-structural protein 3 of hepatitis C virus as modulator of protein phosphorylation mediated by PKA and PKC: evidences for action on the level of substrate and enzyme |
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Authors: | P Borowski M Heiland H Feucht R Laufs |
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Institution: | Bernhard-Nocht-Institut für Tropenmedizin, Abt. Virologie, Hamburg, Federal Republic of Germany, DE Nordwestdeutsche Kieferklinik, Mund-, Kiefer-, Gesichtschirurgie, Universit?tskrankenhaus Eppendorf, Hamburg, Federal Republic of Germany, DE Institut für Medizinische Mikrobiologie und Immunologie, Universit?tskrankenhaus Eppendorf, Hamburg, Federal Republic of Germany, DE
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Abstract: | Summary. Generally, the maximum activities of the protein kinases A* (PKA) and C (PKC) show an optimum value for their substrate concentrations rather than a saturation curve; at high substrate
concentrations, the kinase activity is completely abolished. The C- and N-truncated form of the non-structural protein 3 (NS3)
of hepatitis C virus (HCV) (HCV-polyprotein-(1 189–1 525)) abolishes the inhibiting effect of the substrate, yielding saturable
Michaelis-Menten kinetics of PKA and its catalytical domain (C subunit). In contrast, HCV-polyprotein-(1 189–1 525) activates
PKC with increasing Vmax, while it abolishes the substrate inhibition of its catalytical domain (M-kinase) through a mechanism analogous to that of
PKA and C subunit. PKC isoforms α, β and γ investigated are similarly activated by HCV-polyprotein-(1 189–1 525). Our data
suggest that NS3 attenuates the substrate inhibition through a generalized mechanism operating mainly on the substrate level
that directly results from a specific protein-protein interaction. In the case of the PKC, an additional kinase activating
mechanism operates on the enzyme level. Both actions of NS3, the attenuation of the substrate inhibition and the activation
of PKC, could not be explained by classical means that predict autophosphorylation to enhance the rate of substrate phosphorylation.
The results are discussed in view of similar activities displayed by matchmakers and some molecular chaperones.
Received June 15, 1998 Accepted October 30, 1998 |
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