The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein

Clin Exp Immunol. 2006 May;144(2):342-52. doi: 10.1111/j.1365-2249.2006.03071.x.


The complement inhibitor Factor H has three distinct binding sites for C3b and for heparin, but in solution uses specifically the most C-terminal domain, i.e. short consensus repeats (SCR) 20 for ligand interaction. Two novel monoclonal antibodies (mABs C14 and C18) that bind to the most C-terminal domain SCR 20 completely blocked interaction of Factor H with the ligands C3b, C3d, heparin and binding to endothelial cells. In contrast, several mAbs that bind to the N-terminus and to the middle regions of the molecule showed no or minor inhibitory effects when assayed by enzyme-linked immunosorbent assay (ELISA) and ligand interaction assays. This paradox between a single functional binding site identified for native Factor H versus multiple interaction sites reported for deletion constructs is explained by a compact conformation of the fluid phase protein with one accessible binding site. On zymosan particles mAbs C14 and C18 blocked alternative pathway activation completely. Thus demonstrating that native Factor H makes the first and initial contact with the C terminus, which is followed by N terminally mediated complement regulation. These results are explained by a conformational hypothetical model: the native Factor H protein has a compact structure and only one binding site accessible. Upon the first contact the protein unfolds and exposes the additional binding sites. This model does explain how Factor H mediates recognition functions during complement control and the clustering of disease associated mutations in patients with haemolytic uraemic syndrome that have been reported in the C-terminal recognition domain of Factor H.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Binding Sites, Antibody / immunology
  • Complement C3b / immunology
  • Complement C3d / immunology
  • Complement Factor H / genetics
  • Complement Factor H / immunology
  • Complement Pathway, Alternative / immunology
  • Endothelial Cells / immunology
  • Epitopes / immunology
  • Heparin / immunology
  • Humans
  • Ligands
  • Models, Biological
  • Mutation
  • Protein Conformation
  • Zymosan / immunology


  • Antibodies, Monoclonal
  • CFH protein, human
  • Epitopes
  • Ligands
  • Complement C3b
  • Complement C3d
  • Complement Factor H
  • Heparin
  • Zymosan