Key Points
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The complement system is an important part of the humoral immune defence in mammals that is formed by about 35 soluble and cell-surface proteins. Together these proteins enable the host to recognize and clear pathogens and altered host cells. The complement proteins C3 and protease factor B have a central role in the activation pathways of the complement system.
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Recent advances in the structural biology of complement protein C3, factor B and their proteolytic fragments revealed unprecedented insights into the underlying molecular mechanisms of activation and regulation of the complement pathways. Marked conformational rearrangements of C3 and factor B are central to their biological functions.
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The structure of complement protein C3 reveals a large, modular protein consisting of 13 domains with a buried thioester moiety. Proteolytic activation of C3 into C3b induces conformational changes that expose binding sites for a range of ligands, as well as expose and activate the thioester moiety for covalent attachment to target surfaces. The activity of the surface-bound C3b is altered upon further proteolysis, resulting in the unwinding of the connecting CUB domain, in iC3b and finally in C3dg and C3c.
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The complement activation pathways converge in the proteolytic activation of C3 into C3a and C3b by the C3 convertase. Formation of these protease complexes depends on an assembly process, either starting from C3b and pro-enzyme factor B or from the homologues C4b and pro-enzyme C2. Structures of the pro-enzyme factor B, its fragment Bb and the homologous fragment C2a, indicate that formation of this critical protease complex depends a series of intricate conformational changes that unlocks the pro-enzyme activity.
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Irreversible dissociation of the active C3 convertase is an inherent mechanism to stop complement activation. Possibly, a conformational change in the protease fragments Bb or C2a after dissociation of the complex prevents re-association of the fragments to C3b and C4b respectively.
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To protect their cells from the potentially damaging results of complement activation, both host and pathogens have developed several mechanisms to control convertase activity.
Abstract
Complement in mammalian plasma recognizes pathogenic, immunogenic and apoptotic cell surfaces, promotes inflammatory responses and marks particles for cell lysis, phagocytosis and B-cell stimulation. At the heart of the complement system are two large proteins, complement component C3 and protease factor B. These two proteins are pivotal for amplification of the complement response and for labelling of the target particles, steps that are required for effective clearance of the target. Here we review the molecular mechanisms of complement activation, in which proteolysis and complex formation result in large conformational changes that underlie the key offensive step of complement executed by C3 and factor B. Insights into the mechanisms of complement amplification are crucial for understanding host defence and pathogen immune evasion, and for the development of complement-immune therapies.
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Acknowledgements
We thank J. D. Lambris and J. van Strijp for reading the manuscript. This work was financially supported by a 'Pioneer' programme grant to P.G. by the Council of Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW).
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Gros, P., Milder, F. & Janssen, B. Complement driven by conformational changes. Nat Rev Immunol 8, 48–58 (2008). https://doi.org/10.1038/nri2231
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DOI: https://doi.org/10.1038/nri2231
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