The 4 functional segments of Factor H: Role in physiological target recognition and contribution to disease

Abstract Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified 4 distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and heparin sites. Three segments are linked to diseases. The regulatory segment is affected in C3 glomerulopathy and antineutrophil cytoplasmic antibody–associated vasculitis. The second segment includes the Y402H polymorphism of age-related macular degeneration, is associated with different types of cancer, and is targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome, in FHR1:FHR3 deficient and autoantibody–positive hemolytic uremic syndrome form and is exploited by pathogens. Factor H function is modulated by Factor H like protein 1 and FHR1, 2 plasma proteins that share segments with Factor H. This interplay is critical for fine-tuning local complement. Understanding Factor H’s physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides insights into disease mechanisms and provides opportunities for therapeutic intervention by using full-length Factor H, its fragments, or complement-modulatory compounds.