Dimerization of complement factor H-related proteins modulates complement activation in vivo

Abstract

The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related ( CFHR ) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

“…Moreover, the CFHR3-1Δ resulted in the absence of CFHR1 protein, which was recently shown to function as a competitive antagonist of CFH. 33 Therefore, higher CFH levels, together with the absence of antagonist (CFHR1 protein), resulted in the robust complement inhibition, which is represented by the higher circulating C3 and lower C3a that we observed in patients with IgAN with the rs6677604-AA genotype and CFHR3-1D. In accordance with our findings, Yang et al 34 reported that rs3753394 in CFH was associated with circulating C3 levels.…”

“…46 In this study, we found that variants in CFH, CFHR3, and CFHR1 (rs6677604-A allele or CFHR3-1D) were associated with higher CFH levels. Because genetic deletion of CFHR3 and CFHR1 was reported to lead to absence of these proteins 10 and because CFHR1 was a competitive antagonist of CFH to modulate complement activation, 33 higher CFH levels together with the absence of antagonist (CFHR1 protein) resulted in the robust complement inhibition represented by higher circulating C3 and lower C3a. Furthermore, the associations between mesangial C3 deposition and circulating CFH levels as well as genetic variants suggested that variants in CFH, CFHR3, and CFHR1 influenced the formation and deposition of pathogenic immune complexes in IgAN.…”

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

“…18 Using a hemolysis assay with guinea pig erythrocytes as the complement-activating surface, two independent studies documented that FHR1, by forming homodimers or heterodimers with FHR2 or FHR5, acquires avidity for cell-bound complement fragments and competes with FH for ligand binding. 17,19 The observation here that the addition of purified FHR1 from control subjects to human serum did not induce hemolysis of sheep erythrocytes and did not increase complement deposition on microvascular endothelial cells discloses that the capability of FHR1 to compete with FH-binding is restricted to only a subset of self-surfaces depending on the relative affinity of FHR1 and FH to their specific cell surface ligands. Published data that the Ser1191Leu/Val1197Ala FH mutant and the FH/ FHR1 hybrid, in which the C terminus of FH is identical to the C terminus of FHR1, failed to bind and protect sheep erythrocytes from complement lysis and resulted in aHUS document that the two amino acidic differences between SCR5 (Leu290 and Ala296) of FHR1 and SCR20 (Ser1191 and Val1197) of FH are enough to dictate the affinity differences between the two proteins on aHUS-relevant surfaces.…”

The role of the alternative pathway of complement activation in glomerular diseases

“…In the recent study performed by van Beek et al, CFHR1-CFHR5 and CFHR2-CFHR5 heterodimers were absent in human plasma [42]. It has to be underlined that the results of this report are in opposition to the former (based on in vitro assays) suggesting that dimerization confers avidity for tissue-bond complement fragments and thus may enhance complement deregulation [38]. According to the latter study, serum levels of CFHR-1-CFHR1, CFHR-1-CFHR2, CFHR-2-CFHR2, and CFHR-5-CFHR5 dimers were low compared to CFH, which circulates at a 10-to [45], modified 200-fold molar excess.…”

“…First, CFHRs may compete with CFH for the same binding site on C3b, but because of lack of the regulatory domains, they do not exhibit both cofactor and decay acceleration activity. This process was called complement deregulation, and so far, CFHR1, CFHR2, and CFHR5 have been described to be a competitive antagonist of CFH [37][38][39][40]. Secondly, CFHR5 may deregulate complement indirectly by competing with CFH in binding to other than C3b physiological ligands, including pentraxin PTX3, CRP and extracellular matrix [36].…”