Limited proteolysis of HMW kininogen by plasma kallikrein in man--evidence for a processing mechanism different from the bovine system.

The limited proteolysis of human HMW kininogen by plasma kallikrein has been studied. Kallikrein liberated bradykinin from HMW kininogen (Mr 114 kDa) and generated a two-chain molecule with a heavy chain of Mr 63 kDa and a light chain of Mr 58 kDa interconnected via a single disulfide bridge. As proteolysis proceeded, a step-wise processing of the initially formed light chain occurred giving rise to modified light chains of Mr 45 and 41 kDa. Sequence analysis indicated that two polypeptides had been cleaved from the amino- and carboxy-terminal parts of the 58 kDa light chain. Major part of the histidine-rich peptide which is critical to surface binding of HMW kininogen was kept in the shortened light chains. These findings are consistent with the observation that trimming of the human HMW kininogen does not abolish its procoagulant activity. By contrast, the bovine HMW kininogen is inactivated due to removal of the entire histidine-rich peptide. Hence, the proteolytic processing mechanisms for HMW kininogen are distinct in the human and the bovine contact phase activation systems.