The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity.
Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the factor H (fH)-Ile(62) polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses, we show here that the protective fH-Ile(62) variant binds more efficiently to C3b than fH-Val(62) and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile(62) in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data, we conclude that the protective effect of the fH-Ile(62) variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyze inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile(62) polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulation.
Tortajada
Agustín
A
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain.
Montes
Tamara
T
Martínez-Barricarte
Rubén
R
Morgan
B Paul
BP
Harris
Claire L
CL
de Córdoba
Santiago Rodríguez
SR
D003179:Complement C3b / Q000378:metabolism*; D011415:Complement Factor B / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D011110:Polymorphism, Genetic; D011485:Protein Binding; D020349:Surface Plasmon Resonance
C493495:CFH protein, human; D007532:Isoleucine; D003179:Complement C3b; D017242:Complement Factor H; D011415:Complement Factor B