Human factor H-related protein 2 (CFHR2) regulates complement activation

PLoS One. 2013 Nov 18;8(11):e78617. doi: 10.1371/journal.pone.0078617. eCollection 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Complement C3 / chemistry
  • Complement C3 / genetics
  • Complement C3 / metabolism
  • Complement C3-C5 Convertases / chemistry
  • Complement C3-C5 Convertases / genetics
  • Complement C3-C5 Convertases / metabolism
  • Complement C3b Inactivator Proteins / chemistry
  • Complement C3b Inactivator Proteins / genetics
  • Complement C3b Inactivator Proteins / metabolism*
  • Complement Factor H / chemistry
  • Complement Factor H / genetics
  • Complement Factor H / metabolism
  • Complement Factor I / chemistry
  • Complement Factor I / genetics
  • Complement Factor I / metabolism
  • Complement Pathway, Alternative / physiology*
  • Humans
  • Protein Multimerization / physiology
  • Protein Structure, Tertiary
  • Proteolysis*
  • Repetitive Sequences, Amino Acid


  • CFHR1 protein, human
  • CFHR2 protein, human
  • Complement C3
  • Complement C3b Inactivator Proteins
  • Complement Factor H
  • Complement C3-C5 Convertases
  • Complement Factor I

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (DFG, Sk 46, Zi 432), Germany. HUE, DB and QC are doctoral researchers at the International Leibniz Research School (ILRS), part of the Jena school of Microbial Communication (JSMC), Jena, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.