Research Projects

The alternative pathway (AP) of complement is constitutively active, and therefore lack of its proper regulation results in uncontrolled activation. Notably, it can be activated both in the fluid phase and on the cell surface. The efficient control of this pathway is primarily mediated by complement factor H. How factor H regulates AP on the cell surface has been studied well, but how it regulates this pathway in solution is far from clear. Genotype-phenotype correlation studies have shown that the lack of fluid phase regulation of AP by factor H leads to C3 glomerulopathy (C3G), a kidney disease. In this proposal, by combining mutagenesis, biochemical studies, X-ray crystallography and cryo-EM studies we propose to decipher the molecular mechanism behind the fluid-phase AP regulation by factor H. This proposal will test the following hypotheses: 1) That the regulation mechanism of the alternative pathway by factor H differs between the fluid phase and the cell surface, and 2) That the physically distinct sites in FH1-4 are involved in imparting cofactor and decay-accelerating activities. We believe that the proposed studies will provide valuable insights into the regulatory mechanism of factor H in solution, the absence of which results in the development of a disease.