Factor B is the central protease of the complement system of immune defense. Here, we present the crystal structure of human factor B at 2.3-Å resolution, which reveals how the five-domain proenzyme is kept securely inactive. The canonical activation helix of the Von Willebrand factor A (VWA) domain is displaced by a helix from the preceding domain linker. The two helices conformationally link the scissile-activation peptide and the metal ion–dependent adhesion site required for binding of the ligand C3b. The data suggest that C3b binding displaces the three N-terminal control domains and reshuffles the two central helices. Reshuffling of the helices releases the scissile bond for final proteolytic activation and generates a new interface between the VWA domain and the serine protease domain. This allosteric mechanism is crucial for tight regulation of the complement-amplification step in the immune response.
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We thank the European Synchrotron Radiation Facility for providing synchrotron radiation facilities and the beamline scientists at ID-14-EH4 for their help with data collection. This work was supported by a 'Pionier' program grant (P.G.) of the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW).
The authors declare no competing financial interests.
Stereo figure showing electron density (PDF 695 kb)
Activation state of the VWA domain (PDF 299 kb)
The serine protease domain catalytic center (PDF 177 kb)
The CCP triad arrangementF (PDF 400 kb)
The Mg2+-dependent C3b-binding site (PDF 366 kb)
Analysis of CCP domains 1–3 (PDF 37 kb)
Contacts between domains CCP1–CCP3 and the VWA and SP domains (PDF 43 kb)
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Milder, F., Gomes, L., Schouten, A. et al. Factor B structure provides insights into activation of the central protease of the complement system. Nat Struct Mol Biol 14, 224–228 (2007) doi:10.1038/nsmb1210
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