Factor B structure provides insights into activation of the central protease of the complement system

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Abstract

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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Figure 1: C3 convertase formation and crystal structure of complement factor B.
Figure 2: Regulatory elements in the VWA domain.
Figure 3: Domain orientations in factor B and Bb.

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Protein Data Bank

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Acknowledgements

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).

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Correspondence to Piet Gros.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Stereo figure showing electron density (PDF 695 kb)

Supplementary Fig. 2

Activation state of the VWA domain (PDF 299 kb)

Supplementary Fig. 3

The serine protease domain catalytic center (PDF 177 kb)

Supplementary Fig. 4

The CCP triad arrangementF (PDF 400 kb)

Supplementary Fig. 5

The Mg2+-dependent C3b-binding site (PDF 366 kb)

Supplementary Table 1

Analysis of CCP domains 1–3 (PDF 37 kb)

Supplementary Table 2

Contacts between domains CCP1–CCP3 and the VWA and SP domains (PDF 43 kb)

Supplementary Methods (PDF 56 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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