Complement C3 recognition by C3 convertases
Changhao Jia1,2,3,4,5,6, Xiaoke Yang7, Ming-Hui Zhao1,2,3,4,5
1Renal Division, Department of Medicine, Peking University First Hospital, Beijing, P.R. China.
Insights
Structural insights into complement activation reveal how key enzymes C4b2a and C3bBb bind complement component 3 (C3). This study elucidates molecular mechanisms in the classical, lectin, and alternative pathways.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- The complement system is crucial for immunity, with its dysregulation linked to various diseases.
- Complement activation involves classical, lectin, and alternative pathways converging at complement component 3 (C3).
- The precise mechanisms of C3 recognition by convertase complexes are not fully understood.
Purpose of the Study:
- To elucidate the structural basis of C3 recognition by the C4b2a convertase.
- To understand conformational changes during classical and lectin pathway convertase maturation.
- To uncover the structural features of C3bBb-properdin and its role in the alternative pathway.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine high-resolution structures.
- Structures were obtained for the C4b2a-C3 Michaelis complex, C4b2 zymogen states, and C3bBb-properdin-C3 complex.
Main Results:
- The structure of the C4b2a-C3 Michaelis complex reveals how C4b2a engages C3.
- Structures of C4b2 zymogen show conformational changes during convertase maturation.
- The C3bBb-properdin-C3 structure highlights unique substrate binding and properdin's stabilization role.
Conclusions:
- Provides comprehensive mechanistic insights into complement activation pathways.
- Elucidates the structural mechanisms of C3 cleavage by classical, lectin, and alternative pathway convertases.
- Offers a structural foundation for understanding complement-related diseases and therapeutic development.
Abstract:
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.
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