Initiation of the alternative complement pathway due to spontaneous hydrolysis of the thioester of C3

Abstract

Initiation of the alternative pathway of complement involves the random attachment of C3b on all biological particles in contact with plasma. This process requires continuous proteolytic generation of metastable C3b. The responsible protease arises as a result of conformational changes in C3 that occur upon thioester hydrolysis. The product, C3(H2O), is functionally C3b-like and forms a C3 convertase with Factors B and D. The resulting biomolecular enzyme, C3(H2O),Bb, is a serine protease that cleaves C3 generating metastable C3b. The rate of spontaneous generation of C3(H2O) under physiological conditions is between 0.2 and 0.4%/hr. C3(H2O),Bb produces only three to five metastable C3b molecules per enzyme before being inactivated by regulatory proteins. The thioester bond in metastable C3b has been estimated to be 10(10) times more reactive than that in native C3 and mediates attachment of C3b to biological particles. Once bound, C3b is subject to two competing processes: (1) inactivation and (2) a chain reaction-like amplification process that can deposit large numbers of C3b molecules on the particles within a very short period of time after the initial C3b binds. On activators of the alternative pathway, inactivation of C3b is restricted and amplification of C3b results in activation of the cytolytic pathway of complement.