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Control of the function of substrate-bound C4b-C3b by the complement receptor Cr1
Insights
The complement receptor 1 (CR1) acts as a cofactor for degrading complement fragments C4b and C3b. Its activity is enhanced by the presence of other complement fragments, suggesting efficient control of complement activity on cell surfaces.
Area of Science:
- Immunology
- Complement System Biology
Background:
- Complement fragments C3b and C4b are primary ligands for the membrane receptor CR1.
- CR1 is a known cofactor for factor I-mediated breakdown of C3b.
Purpose of the Study:
- To investigate CR1's role in C4b degradation.
- To explore the modulatory effects of C3b and C4b on each other's degradation by CR1.
Main Methods:
- Enzymatic assays measuring the breakdown of C3b and C4b.
- Use of cell intermediates (EAC14, EAC1423) to study complement fragment interactions.
- Comparison of CR1 cofactor activity with C4-binding protein (C4bp).
Main Results:
- CR1 significantly promotes the degradation of C4b into C4c and C4d, with cofactor activity 1000-fold greater than C4bp.
- The degradation of C4b by CR1 is enhanced by the presence of neighboring C3b.
- Conversely, C3b degradation is enhanced by neighboring C4b when CR1 is the cofactor.
- CR1's cofactor activity for C4b degradation is inhibited by C3b when C4bp is the cofactor.
Conclusions:
- CR1 is a potent cofactor for C4b degradation, superior to C4bp.
- The interaction between C3b and C4b in proximity to CR1 enhances their respective degradation, suggesting a cooperative mechanism.
- These findings highlight CR1's crucial role in regulating complement activity on cell surfaces under physiological conditions.
Abstract:
The complement fragments C3b and C4b are the main ligands for the membrane receptor CR1. We showed elsewhere that CR1 functions as an essential cofactor for the factor I-mediated enzymatic breakdown of membrane-bound C3b (*C3b) into C3c and * C3dg . One of the main findings of the present paper is that 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 is 10(3)-fold greater than that of the serum cofactor C4-binding protein ( C4bp ). An additional finding is that 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. For example, 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. Conversely, when the number of *C3b molecules on EAC1423 is relatively small (or when EAC1423 has 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. Indeed, 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 . Taken together, these findings suggest that degradation of *C4b will be more effective 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.