Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway.

Abstract

In this study, the physiological role of properdin and the differential subunit composition of the solid phase enzymes of the alternative complement [C] pathway were explored. Cell-bound C3 and C5 convertase differ in their C3b requirement. Apparently 1 molecule of C3b is sufficient to allow formation of C3 convertase .**GRAPHIC**. whereas 2 or more are required for generation of C5 convertase .**GRAPHIC**. The spatial distribution of C3b molecules on the cell surface in enzyme formation is apparently critical. While the C3/C5 convertase is fully capable of acting on C5 and thereby initiating the assembly of the cytolytic membrane attack complex, it is exceedingly labile and vulnerable to destruction by the C3b inactivator. Properdin apparently confers a degree of stability upon the labile enzyme and protects its C3 convertase function against enzymatic destruction. To achieve these effects, precursor properdin (pre-P) is recruited in a binding-activation reaction by the labile C3/C5 convertase. Multiple C3b molecules appear to be needed for the formation of properdin-activating principle. Three modes of regulation were described which involve spontaneous dissociation enzymatic degradation by C3b inactivator and disassembly by .beta.1H. The functional differences of pre-P and activated properdin (.hivin.P) were delineated, pre-P displaying a weak affinity for C3b and .hivin.P the capacity of strong interaction, .hivin.P generating a soluble C3 convertase in serum and pre-P being unable to do so. Because of the profound differences between native pre-P and the laboratory product .hivin.P, the question was raised as to whether soluble .hivin.P represents an unphysiological form of the protein. In vitro properdin recruitment constitutes the terminal event of the properdin pathway. Properdin augments the function of C3/C5 convertase without changing its substrate specificity.