Human Factor H-related Protein 5 (FHR-5)

Abstract

A novel human plasma protein has been identified as a universal component of complement deposits, when complement is detected immunohistochemically in vivo. The protein is homologous to complement factor H and related proteins and has been designated factor H-related protein 5 (FHR-5). FHR-5 was identified by a monoclonal antibody raised using pathologic human glomerular preparations as the immunogen. FHR-5 was purified by affinity chromatography from complementlysed erythrocytes, and the peptide sequence was obtained. The cDNA was cloned from a human liver library, and FHR-5 was deduced to be a protein containing 551 amino acids organized into nine short consensus repeat motifs. The short consensus repeats of FHR-5 show homology to Factor H and to other Factor H-related proteins, with some unique features demonstrated. Recombinant FHR-5, expressed in insect cells, was shown to bind C3b in vitro. The strong association of FHR-5 with tissue complement deposits in vivo suggests that this additional member of the Factor H family of proteins has a function in complement regulation.

Isolation and Characterization of a Novel Rat Factor H-related Protein That Is Up-regulated in Glomeruli under Complement Attack

“…4). By comparison to the areas mapped in human factor H that confer binding activity for C3b, FHR-5 has two potential binding sites for C3b (8,10), and therefore, it is not surprising that human FHR-5 has the ability to bind C3b (26). The same basic SCR structure and capacity to bind C3b is true for rat FHR, as we have shown here.…”

“…This was possible because the K2.254 monoclonal antibody raised against diseased glomeruli reacted with FHR-5 and was used to isolate FHR-5 for peptide determination, knowledge of which was then used in a cloning strategy. In these studies, it was shown that FHR-5 mRNA could be produced by the liver and that FHR-5 protein could deposit on guinea pig erythrocytes during complement activation by whole serum (26). In follow-up studies on FHR-5, it was clear that FHR-5 was a prominent component of glomerular immune deposits, being present in 100% of cases of membranous nephropathy, IgA nephropathy, and lupus nephritis (27).…”

“…The next members to be cloned were FHRs 1-4 by virtue of their nucleotide similarity to the "parent" factor H (42)(43)(44). In contrast, FHR-5 was identified because it was a component of immune deposits in glomerular diseases (26). This was possible because the K2.254 monoclonal antibody raised against diseased glomeruli reacted with FHR-5 and was used to isolate FHR-5 for peptide determination, knowledge of which was then used in a cloning strategy.…”

“…FHRs 1-4 contain four to five SCRs, whereas FHR-5 is the longest with nine SCRs. Each of these proteins have similar C-terminal SCRs, with homology to SCRs 19 -20 of factor H (7,26,37). Of these, human FHR-5 is most similar to rat FHR, as its nine SCRs have up to 79% homology to corresponding SCRs in rat FHR (Fig.…”

“…other one of these monoclonal antibodies was used to clone the fifth FHR (FHR-5) (26). Although FHR-5 was not expressed in normal glomeruli, it was uniformly expressed in the glomeruli of patients with immunologically mediated diseases, such as membranous nephropathy (27).…”