A mechanism for the spontaneous activation of the first component of complement, C1, and its regulation by C1-inhibitor.
We have developed a method to initiate spontaneous activation of the first component of complement in serum, by the removal of C1-inhibitor through complexation with added C1s. Preliminary experiments to test this method using C1 reconstituted from its purified subcomponents led to an unexpected result: pre-incubation of the reassembled subcomponents with C1-inhibitor, followed by its removal with C1s, altered the subsequent pattern of spontaneous activation. Thus, pre-incubation with C1-inhibitor at 37 degrees C for 1 h resulted in sigmoidal activation of C1 with a prolonged lag phase. In contrast, pre-incubation with C1-inhibitor on ice for the same time resulted in subsequent rapid, pseudo first order activation of C1 with a half-life of about 5 min. We have examined the activation kinetics under a variety of conditions, and our data are consistent with a model proposed by Lepow and coworkers in 1965, involving both spontaneous activation and C1 catalyzed activation: (1) C1----k1 C1 (2) C1----k2C1 C1 According to this model, the role of C1-inhibitor is to eliminate the second step by rapidly forming a tight complex with C1 which becomes irreversible at 37 degrees C. When C1s was added to normal human serum, activation at 37 degrees C was also sigmoidal, similar to that of reconstituted C1.
Bianchino
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Department of Chemistry and Biochemistry, University of California, Los Angeles 90024.
Poon
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Schumaker
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D003166:Complement Activating Enzymes / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism; D003167:Complement Activation; D003172:Complement C1 / Q000302:isolation & purification / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D003171:Complement Pathway, Classical; D006801:Humans; D007700:Kinetics; D013696:Temperature
D003172:Complement C1; D003174:Complement C1 Inactivator Proteins; D003166:Complement Activating Enzymes