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

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.