CFH - Complement factor H - human protein (Function)

Overview

Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway.

CuratedUniProtKB

GO molecular function

Heparan sulfate proteoglycan bindingdefinition[GO:0043395]

Evidence 1: Inferred from Direct Assay BHF-UCL

Bivalent and co-operative binding of complement factor H to heparan sulfate and heparin.

Khan S., Nan R., Gor J., Mulloy B., Perkins S.J.

Biochem. J. 444, 417-428 (2012) [Full text:10.1042/BJ20120183] [PubMed:22471560]

FH (Factor H) with 20 SCR (short complement regulator) domains is a major serum regulator of complement, and genetic defects in this are associated with inflammatory diseases. Heparan sulfate is a cell-surface glycosaminoglycan composed of sulfated S-domains and unsulfated NA-domains. To elucidate the molecular mechanism of binding of FH to glycosaminoglycans, we performed ultracentrifugation, X-ray scattering and surface plasmon resonance with FH and glycosaminoglycan fragments. Ultracentrifugation showed that FH formed up to 63% of well-defined oligomers with purified heparin fragments (equivalent to S-domains), and indicated a dissociation constant K(d) of approximately 0.5 μM. Unchanged FH structures that are bivalently cross-linked at SCR-7 and SCR-20 with heparin explained the sedimentation coefficients of the FH-heparin oligomers. The X-ray radius of gyration, R(G), of FH in the presence of heparin fragments 18-36 monosaccharide units long increased significantly from 10.4 to 11.7 nm, and the maximum lengths of FH increased from 35 to 40 nm, confirming that large compact oligomers had formed. Surface plasmon resonance of immobilized heparin with full-length FH gave K(d) values of 1-3 μM, and similar but weaker K(d) values of 4-20 μM for the SCR-6/8 and SCR-16/20 fragments, confirming co-operativity between the two binding sites. The use of minimally-sulfated heparan sulfate fragments that correspond largely to NA-domains showed much weaker binding, proving the importance of S-domains for this interaction. This bivalent and co-operative model of FH binding to heparan sulfate provides novel insights on the immune function of FH at host cell surfaces.

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IDABHF-UCL

Heparin bindingdefinition[GO:0008201]

Evidence 1: Inferred from Direct Assay BHF-UCL

Bivalent and co-operative binding of complement factor H to heparan sulfate and heparin.

Khan S., Nan R., Gor J., Mulloy B., Perkins S.J.

Biochem. J. 444, 417-428 (2012) [Full text:10.1042/BJ20120183] [PubMed:22471560]

FH (Factor H) with 20 SCR (short complement regulator) domains is a major serum regulator of complement, and genetic defects in this are associated with inflammatory diseases. Heparan sulfate is a cell-surface glycosaminoglycan composed of sulfated S-domains and unsulfated NA-domains. To elucidate the molecular mechanism of binding of FH to glycosaminoglycans, we performed ultracentrifugation, X-ray scattering and surface plasmon resonance with FH and glycosaminoglycan fragments. Ultracentrifugation showed that FH formed up to 63% of well-defined oligomers with purified heparin fragments (equivalent to S-domains), and indicated a dissociation constant K(d) of approximately 0.5 μM. Unchanged FH structures that are bivalently cross-linked at SCR-7 and SCR-20 with heparin explained the sedimentation coefficients of the FH-heparin oligomers. The X-ray radius of gyration, R(G), of FH in the presence of heparin fragments 18-36 monosaccharide units long increased significantly from 10.4 to 11.7 nm, and the maximum lengths of FH increased from 35 to 40 nm, confirming that large compact oligomers had formed. Surface plasmon resonance of immobilized heparin with full-length FH gave K(d) values of 1-3 μM, and similar but weaker K(d) values of 4-20 μM for the SCR-6/8 and SCR-16/20 fragments, confirming co-operativity between the two binding sites. The use of minimally-sulfated heparan sulfate fragments that correspond largely to NA-domains showed much weaker binding, proving the importance of S-domains for this interaction. This bivalent and co-operative model of FH binding to heparan sulfate provides novel insights on the immune function of FH at host cell surfaces.

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IDABHF-UCL

Protein bindingdefinition[GO:0005515]

Evidence 1: Inferred from Physical Interaction IntAct

Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes.

Haapasalo K., Jarva H., Siljander T., Tewodros W., Vuopio-Varkila J., Jokiranta T.S.

Mol. Microbiol. 70, 583-594 (2008) [Full text:10.1111/j.1365-2958.2008.06347.x] [PubMed:18627465]

The main virulence factor of group A streptococcus (GAS), M protein, binds plasma complement regulators factor H (FH) and FH-like protein 1 (FHL-1) leading to decreased opsonization. The M protein binding site on FH is within domain 7 in which also the age-related macular degeneration (AMD)-associated polymorphism Y402H is located. We studied if FH allotypes 402H and 402Y have different binding affinities to GAS. Plasma-derived FH allotype 402H and its recombinant fragment FH5-7(402H) showed decreased binding to several GAS strains. Growth of GAS in human blood taken from FH(402H) homozygous individuals was decreased when compared with blood taken from FH(402Y) homozygous individuals. The effect of the allotype 402H can be explained by combining the previous M protein mutagenesis data and the recently published crystal structure of FH6-8. In conclusion the data indicate that the AMD-associated allotype 402H leads to diminished binding of FH to GAS and increased opsonophagocytosis of the bacteria in blood. These results suggest that the homozygous presence of the allele 402H could be associated with decreased risk for severe GAS infections offering an explanation for the high frequency of the allele despite its association with visual impairment.

Erratum in:

Mol Microbiol. 83(6), 1285-6 (2012 Mar)

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IPIIntAct

GO biological process

Complement activationdefinition[GO:0006956]

Evidence 1: Traceable Author Statement PINC

Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.

Ault B.H., Schmidt B.Z., Fowler N.L., Kashtan C.E., Ahmed A.E., Vogt B.A., Colten H.R.

J. Biol. Chem. 272, 25168-25175 (1997) [PubMed:9312129]

The synthesis and secretion of factor H, a regulatory protein of the complement system, were studied in skin fibroblasts from an H-deficient child who has chronic hypocomplementemic renal disease. In normal fibroblasts, factor H transcripts of 4.3 and 1.8 kilobase pairs (kb) encode a 155-kDa protein containing short consensus repeat (SCR) domains 1-20 and a 45-kDa protein which contains SCRs 1-7, respectively. The patient's fibroblasts expressed normal amounts of the 4.3- and 1.8-kb messages constitutively and after tumor necrosis factor-alpha/interferon-gamma stimulation. Lysates of [35S]methionine-labeled fibroblasts from the patient contained the 155- and 45-kDa H polypeptides, but secretion of the 155-kDa protein was blocked; the 45-kDa protein was secreted with normal kinetics. The patient's plasma lacked the 155-kDa protein but contained the small form of H. Moreover, in fibroblasts the retained 155-kDa factor H protein was not degraded, even after 12 h. Immunoflourescent staining and confocal microscopic imaging of the patient's fibroblasts indicated that factor H was retained in the endoplasmic reticulum. Sequence analysis of reverse transcription-polymerase chain reaction products (the entire coding region) and genomic DNA revealed a T1679C substitution on one allele and a G2949A substitution on the other (C518R mutation in SCR 9 and C991Y mutation in SCR 16, respectively). Both mutations affect conserved cysteine residues characteristic of SCR modules and therefore predict profound changes in the higher order structure of the 155-kDa factor H protein. These data provide the first description of a molecular mechanism for factor H deficiency and yield important insights into the normal secretory pathway for this and other plasma proteins with SCR motifs.

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TASPINC

Complement activation, alternative pathwaydefinition[GO:0006957]

IEAUniProtKB KW

Pathways

According to KEGG, this protein belongs to the following pathways:

Complement and coagulation cascades hsa04610+3075

Staphylococcus aureus infection hsa05150+3075

According to Reactome, this protein belongs to the following pathway:

Immune System REACT_6900

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Function

Keywords

neXtProt