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-reacti ve 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 o f fibrinogen (340 kDa) to non-clottable products and generates termina l products with apparent molecular mass values of 270 kDa, 200 kDa, 10 0 kDa and less than 40 kDa through cleavage of all three of the consti tuent chains. Characteristics of fibrinogenolysis by this neutrophil p rotease are cleavage of the bond between amino acids valine and glutam ic acid at positions 21 and 22 respectively from the N-terminus of the Aalpha chain to release an Aalpha1-21 peptide, digestion of the Bbeta chain at positions within the C-terminus, and proteolysis of the bond between amino acids isoleucine and glycine at positions 394 and 395 r espectively from the N-terminus of the gamma chain. This generates pro ducts 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 mem brane protease in vivo could be important for the regulation of fibrin deposition at sites of inflammation, and may contribute to the report ed plasma levels of the Aalpha1-21 peptide.