Control of the function of substrate-bound C4b-C3b by the complement receptor Cr1.

Abstract

The complment fragments C3b [complement component 3b] and C4b are the main ligands for the membrane receptor CR1. CR1 functions as an essential cofactor for the factor I-mediated enzymatic breakdown of membrane-bound C3b (*C3b) into C3c and *C3dg. CR1 also promotes the degradation of bound C4b (*C4b) into C4c and *C4d. On a weight basis, the cofactor activity of CR1 in the cleavage of *C4b present on the cell intermediate EAC14 [antibody sensitized sheep erythrocyte bound to complement C1 and C4] is 103-fold greater than that of the serum cofactor C4-binding protein (C4bp). The effect of CR1 on either *C3b or *C4b is modulated by the presence of the other ligand in its vicinity; that is, *C4b degradation by CR1 plus I is enhanced by neighboring *C3b and vice versa. Upon uptake of optimal amounts of *C3b onto EAC142 and the assembly of the C3-convertase EAC1423, the activity of CR1 in generating C4c is enhanced 5-10 times further. When the number of *C3b molecules on EAC1423 is relatively small (or when EAC1423 had been converted by I plus H into EAC1423i), the presence of neighboring *C4b enhances the conversion of *C3b (or *iC3b) into C3c plus *C3dg. The enhancing effect of *C3b on the cleavage of *C4b by I is observed only if the cofactor of this reaction is CR1. The activity of I or I plus C4bp on *C4b is significantly inhibited when *C3b is fixed and the main product of the reaction is *iC4b. Degradation of *C4b will be more effecive when enough C3b molecules are fixed nearby, thus facilitating the interaction of *C4b*3b clusters with CR1-bearing cells, and that under physiological conditions. *C4b activity can be efficiently controlled by CR1.