Inhibition of plasmin, urokinase, tissue plasminogen activator, and C1S by a myxoma virus serine proteinase inhibitor.
The myxoma and malignant rabbit fibroma poxviruses are lethal tumorigenic viruses of rabbits whose virulence is modulated by the production of a virus-encoded secreted serine proteinase inhibitor, SERP-1. This viral protein was detected in medium harvested from myxoma and malignant rabbit fibroma virus-infected cells, and its inhibitory profile has been characterized by gel and kinetic analysis. SERP-1 forms complexes with and inhibits the human fibrinolytic enzymes plasmin, urokinase, and two-chain tissue-type plasminogen activator (association rate constants 3.4 x 10(4), 4.3 x 10(4), and 3.6 x 10(4) M-1 s-1 respectively). It is also able to inhibit C1S, the first enzyme in the complement cascade with an association rate constant which was unaffected by the addition of heparin (1.3 x 10(3) M-1 s-1). SERP-1 acts as a substrate for and is cleaved by thrombin, porcine trypsin, human neutrophil elastase, porcine pancreatic elastase, thermolysin, subtilisin, bovine alpha-chymotrypsin, and factor Xa. Incubation with kallikrein and cathepsin G had no effect. The structure of SERP-1 has been modeled on other members of the serpin family which revealed the characteristic serpin architecture apart from the absence of the D-helix. Structural analysis and kinetic assays demonstrate that the absence of this region does not prevent inhibitory activity and furthermore allow the identification of cysteine residues involved in internal and intermolecular disulfide bonding.
Lomas
D A
DA
Department of Haematology, University of Cambridge, United Kingdom.
Evans
D L
DL
Upton
C
C
McFadden
G
G
Carrell
R W
RW
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D005814:Genes, Viral; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009233:Myxoma virus / Q000235:genetics / Q000502:physiology*; D017433:Protein Structure, Secondary; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000737:chemistry* / Q000235:genetics* / Q000494:pharmacology*; D013379:Substrate Specificity; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*
D015843:Serpins; D014764:Viral Proteins; D012697:Serine Endopeptidases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator