Complement Gene Variants Define the Conformational Dynamics of C3 Convertase

Current understanding of the structure, function, and molecular dynamics of the alternative pathway C3-convertase has been shaped by the clinical impact of genetic variants in complement genes. Characterizing the functional impact of different mutations not only provides patient-specific insights into the pathogenic mechanisms underlying a number of complement-mediated diseases but, at a broader level, allows us to dissect the molecular underpinnings of protein-protein interactions that drive complement amplification and its control. In this review, we contextualize over 100 variants in C3, CFB, CFD, CFH, and CFI to illustrate how this collective knowledge informs known mechanisms of complement biology and illuminates gaps that remain to be defined.