A new function of the activated third component of complement: binding to C5, an essential step for C5 activation |
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| Authors: | W Vogt G Schmidt B Von Buttlar L Dieminger |
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| Abstract: | Incubation of factor B, factor [unk]D, (properdin) and C3b—or of C1[unk]s, C4b and C2—with C3 and/or C5 in a fluid system leads to the generation of C3 cleaving activity while C5 remains unaffected. C5 can be cleaved—activated—when in addition to the enzyme-generating components of either pathway C3b is present which has been fixed to a solid surface immediately after its release from C3 by a surface-fixed enzyme. This has been demonstrated with three C3b-carrying solids: agarose to which C3b was fixed after cleavage of C3 by agarose-coupled trypsin (Ag-C3b), zymosan incubated with human serum (Z-C3b) and sheep red cells in the state EAC43. C3b fixed to these surfaces after release in the fluid phase by soluble enzymes does in general not support C5 cleavage. C3b species active in C5 cleaving processes differ from those inactive by having a newly discovered property: active C3b is capable of reversibly binding C5. Fluid C3 convertase C3b[unk]B cleaves C5 in the presence of surface-fixed active C3b also under conditions under which it cannot interact with the latter. This indicates that two C3b molecules having different functions are involved in this system, one which is incorporated in the enzyme complex and another which binds and thereby prepares C5 for cleavage. The binding requires a special configuration of C3b which is preserved only by fixation immediately after its generation from C3. Efficient binding is possible only when C3b is free of other ligands such as factor B or properdin; these components interfere with binding and cleavage of C5 when having access to active C3b. C5 cleavage by the convertase of the classical complement pathway, C42, appears to proceed by the same mechanism, i.e. free C42 per se attacks C5 when this is bound to active C3b. It is concluded from the results that C5-cleaving complement enzymes do not differ in composition from C3 convertases. The active C3b which is essential for C5 cleavage, and existent only on surfaces, serves to modulate the substrate configuration to make it accessible to the enzyme. |
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