Complement factor I–C3b complex (CFI–C3b)

The Complement factor I–C3b complex is a fundamental regulatory unit of the complement system, primarily responsible for controlling the alternative pathway's amplification loop. Complement factor I (CFI) is a highly specific serine protease that circulates in an inactive form and becomes enzymatically active only when bound to C3b in the presence of a cofactor, such as Factor H or Membrane Cofactor Protein (MCP/CD46) (UniProt: P05155). Upon formation of this complex, CFI performs sequential proteolytic cleavages of the C3b alpha-chain, generating iC3b and subsequently C3dg, which effectively halts the formation of C3 and C5 convertases (PubMed: 22394454). This regulation is vital for protecting host cells from accidental complement-mediated lysis and chronic inflammation. Genetic variants that reduce CFI levels or impair the formation of the CFI–C3b complex are major risk factors for geographic atrophy secondary to age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS) (PubMed: 31533975). Consequently, the complex is a high-priority therapeutic target, with investigational gene therapies like GT005 aiming to increase local CFI production to restore homeostatic C3b degradation in the retina (ClinicalTrials.gov: NCT03846193).

Other names

C3b-CFI complexFactor I-C3b complexC3b/Factor I complexComplement factor I-C3b interaction

Complement factor I acts as a serine protease that, in the presence of cofactors such as Factor H or Membrane Cofactor Protein, cleaves C3b into inactive iC3b, thereby preventing the formation of C3 and C5 convertases and limiting complement-mediated tissue damage (PubMed: 22394454).