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Published on: July 14, 2016
Human factor H-related protein 2 (CFHR2) regulates complement activation
Hannes U Eberhardt1, Denise Buhlmann, Peter Hortschansky
1Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
Insights
Human complement factor H-related protein 2 (CFHR2) acts as a novel regulator of the complement alternative pathway. It inhibits key enzymes and works with factor H to control complement activation, impacting diseases like AMD.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Mutations in the human complement factor H-related (CFHR) gene cluster are linked to diseases like dense deposit disease, CFHR nephropathy, and age-related macular degeneration.
- Dysfunctional CFHR proteins can disrupt complement system regulation, contributing to disease pathogenesis.
Purpose of the Study:
- To identify novel regulators within the CFHR gene cluster.
- To elucidate the mechanism of action of CFHR2 in complement alternative pathway regulation.
Main Methods:
- Biochemical assays to assess complement convertase inhibition.
- Analysis of CFHR2 structure and C3b binding capabilities.
- Investigating the interaction of CFHR2 with Factor H and Factor I.
Main Results:
- CFHR2 identified as a novel alternative pathway complement regulator.
- CFHR2 dimerizes and binds C3b, inhibiting C3 cleavage by convertases.
- CFHR2 functions in concert with Factor H, facilitating Factor I-mediated degradation of C3b.
Conclusions:
- CFHR2 is a significant regulator of the complement alternative and terminal pathways.
- Understanding CFHR2's role provides insights into complement-mediated diseases.
- CFHR2 represents a potential therapeutic target for diseases involving complement dysregulation.
Abstract:
Mutations and deletions within the human CFHR gene cluster on chromosome 1 are associated with diseases, such as dense deposit disease, CFHR nephropathy or age-related macular degeneration. Resulting mutant CFHR proteins can affect complement regulation. Here we identify human CFHR2 as a novel alternative pathway complement regulator that inhibits the C3 alternative pathway convertase and terminal pathway assembly. CFHR2 is composed of four short consensus repeat domains (SCRs). Two CFHR2 molecules form a dimer through their N-terminal SCRs, and each of the two C-terminal ends can bind C3b. C3b bound CFHR2 still allows C3 convertase formation but the CFHR2 bound convertases do not cleave the substrate C3. Interestingly CFHR2 hardly competes off factor H from C3b. Thus CFHR2 likely acts in concert with factor H, as CFHR2 inhibits convertases while simultaneously allowing factor H assisted degradation by factor I.
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