Complement Factor H Related Protein 1

In the complement factor H family, there are five CFHR proteins have been identified, which are divided into two major groups, Group I and Group II, based on their conserved domains. Complement factor H-related protein 1 (CFHR1), a member of Group I CFHR proteins, is a plasma protein circulating in two glycosylated forms at the concentration of 70 to 100 μg/mL. CFHR1 is composed of five short consensus repeat (SCR) domains or complement control protein (CCP) domains. The N-terminal two SCRs, SCR1 and SCR2, exhibit sequence homology to SCR6 and SCR7 of CFH, and share high amino acid identity to SCR1 and SCR2 of CFHR2 and CFHR5. CFHR1 has a dimerization domain at the N-terminus that can form heterodimers with CFHR2 and CFHR5. The sequence of C-terminal SCR3, SCR4, and SCR5 are almost identical to the SCR18-20 of CFH, except for two amino acid differences.

CFHR1 mutations or deficiency are closely related to Hemolytic Uremic Syndrome Atypical 1 and Macular Degeneration Age-Related 1 since CFHR1 is a regulator for complement alternative pathway. However, CFHR1 functions in a manner different from CFH.

1. CFHR1 (SCR1 and SCR2) inhibits C5 cleavage by binding to C3b of the C5 convertase of the complement alternative pathway, not C3 convertase. Thus, the formation of anaphylactic C5a generation and cytolytic membrane attack complex (MAC) are blocked.
2. CFHR1 also inhibits the assembly of the C5bC6 complex, an intermediate product of MAC.
3. The C-terminal SCR3-5 can bind to C3b, C3d, and heparin on the host surface, competing with the binding of complement factor B to C3b thereby inhibiting the complement alternative pathway amplification.

Fig.1 Structure diagram of CFHR1, CFHR 2, and CFHR5. (de Jorge, 2013)

Reference

1. de Jorge, E.G.; et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proceedings of the National Academy of Sciences. 2013, 110(12): 4685-4690.