Complement C3 recognition by C3 convertases

The complement system plays a fundamental role in immunity, and its dysregulation is implicated in numerous human diseases. Activation of complement occurs through three main pathways: classical, lectin, and alternative; which converge at the central component, component of complement 3 (C3). The classical and lectin pathways use the C4b2a convertase to cleave C3 and initiate complement activation, while the alternative pathway uses the C3bBb convertase, which is further stabilized by properdin. The molecular mechanisms governing C3 recognition by these convertase complexes remain incompletely understood. Here, we present the 3.1-angstrom cryo–electron microscopy structure of the C4b2a-C3 Michaelis complex, alongside 2.9- and 3.1-angstrom structures of the C4b2 zymogen in loading and activation states, elucidating the structural basis for C3 engagement by C4b2a and conformational changes during the classical and lectin pathway convertase maturation. Furthermore, a 2.6-angstrom structure of C3bBb-properdin in complex with C3 uncovers unique substrate-binding features of C3bBb and properdin’s stabilizing role in the alternative pathway. These results offer comprehensive mechanistic insights into complement activation.