ROLE OF THE P2-RESIDUE OF COMPLEMENT-1 INHIBITOR (ALA(443)) IN DETERMINATION OF TARGET PROTEASE SPECIFICITY - INHIBITION OF COMPLEMENT AND CONTACT SYSTEM PROTEASES

A dysfunctional C1 inhibitor (C1 INH) from a family in whom the propos itus presented with systemic lupus erythematosus but without angioedem a previously was shown to have diminished inhibitory activity toward i solated C1r and C1s, and intact C1. The mutation was identified as rep lacement of Ala(443) (P2) with Val. This study further analyzed the re activity of this mutant and characterized two mutants with Ser or Asp at this position. Ser at P2 does not interfere with binding of target proteases, However, the mutant with Asp at this position is unable to bind C1r and beta factor XIIa, and also has a decreased rate of reacti on with C1s and kallikrein, Therefore, alteration of polarity alone ha d no effect on binding, while a bulky and/or charged side chain was no t tolerated. Although defective in inhibition of C1r and C1s, the P2A- ->V mutant had acquired the ability to complex with trypsin, It also c ompletely retained the ability to complex with kallikrein and factor X IIa. None of the 10 individuals expressing this mutant protein has eve r had angioedema. This observation, combined with normal inhibition of contact system proteases and defective inhibition of complement prote ases, suggests that angioedema is caused by bradykinin generated from contact system activation.