Fibrinogenolysis by a neutrophil membrane protease generates an A alpha 1-21 fragment.
The 600 kDa neutrophil membrane neutral protease, which had been shown to generate bioactive peptides from the acute-phase reactant C-reactive protein, has now been shown to have fibrinogenolytic activity that is distinct from fibrinogenolysis by plasmin and neutrophil lysosomal enzymes. This protease gradually reduces the apparent molecular mass of fibrinogen (340 kDa) to non-clottable products and generates terminal products with apparent molecular mass values of 270 kDa, 200 kDa, 100 kDa and less than 40 kDa through cleavage of all three of the constituent chains. Characteristics of fibrinogenolysis by this neutrophil protease are cleavage of the bond between amino acids valine and glutamic acid at positions 21 and 22 respectively from the N-terminus of the A alpha chain to release an A alpha 1-21 peptide, digestion of the B beta chain at positions within the C-terminus, and proteolysis of the bond between amino acids isoleucine and glycine at positions 394 and 395 respectively from the N-terminus of the gamma chain. This generates products that lack anticoagulant activity. The thrombin clotting time of the product with an apparent molecular mass of 330 kDa was prolonged, although clot formation was still observed. Loss of coagulability and inability to clot was found with further degradation of fibrinogen to an apparent molecular mass of 290 kDa. Activity of this neutrophil membrane protease in vivo could be important for the regulation of fibrin deposition at sites of inflammation, and may contribute to the reported plasma levels of the A alpha 1-21 peptide.
Kelly
S L
SL
Department of Medicine, University of Cape Town, Observatory, South Africa.
Adams
S A
SA
Robson
S C
SC
Kirsch
R E
RE
Shephard
E G
EG
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D017077:Culture Media, Conditioned; D003599:Cytoskeleton / Q000201:enzymology; D010450:Endopeptidases / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009504:Neutrophils / Q000201:enzymology* / Q000648:ultrastructure; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014238:Trichloroacetic Acid
D000596:Amino Acids; D017077:Culture Media, Conditioned; D005338:Fibrin Fibrinogen Degradation Products; D014238:Trichloroacetic Acid; D005340:Fibrinogen; D010450:Endopeptidases; D013755:Tetradecanoylphorbol Acetate