The structural basis of alternative pathway initiation

The alternative complement pathway (AP) is a crucial part of the human innate immune system and is in first line of defence against invading pathogens. The AP is solicited by pathogen proteins which often interact with human complement factor 3 (C3), the central hub of the complement cascade. This interaction is sufficient to block progression of the complement cascade. Within the AP, the first step of activation involves the conversion of C3 into C3(H2O) which forms the fluid-phase convertase. The aim of the proposal is to resolve for the first time the structure of intact C3(H2O) at near-atomic resolution. Previously we obtained a preliminary structure of C3(H2O) with a small data set at low resolution. The high-resolution structure of C3(H20) will inform about the conformational changes that occur upon cleavage of the thioester bond while the ANA domain (C3a when released) is still being present.