Complement C3 recognition by C3 convertases

The complement system plays a fundamental role in human immunity, and its dysregulation is implicated in numerous diseases. Activation of the complement occurs through three main pathways: classical, lectin, and alternative; which converge at the central component, C3. The classical and lectin pathways utilize the C4b2a convertase to cleave C3 and initiate complement activation, while the alternative pathway employs the C3bBb convertase, which is further stabilized by properdin. The molecular mechanisms governing C3 recognition by these convertase complexes remain incompletely understood. Here, we first present a 3.1 Å cryo-electron microscopy (cryo-EM) structure of the C4b2a–C3 complex, alongside the 2.9 Å and 3.1 Å structures of the C4b2 zymogen in the loading and activation states. These structural snapshots elucidate the structural basis for C3 engagement by C4b2a, and illustrate sequential conformational changes during the classical/lectin pathway convertase maturation. Furthermore, we determine a 2.6 Å cryo-EM structure of the C3bBb–properdin–C3 complex, which uncovers unique substrate-binding features of C3bBb and sheds light on how properdin stabilizes the alternative pathway convertase. These results offer comprehensive mechanistic insights into complement activation.