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Structures of complement component C3 provide insights into the function and evolution of immunity

Nature volume 437, pages 505–511 (2005)Cite this article

Abstract

The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the α2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the α-chain, including movement of a critical interaction site through a ring formed by the domains of the β-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.

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Figure 1: Structures of human complement components C3 and C3c.
Figure 2: Differences in domain arrangements between C3 and C3c.
Figure 3: Domain organization of the α2M family deduced from the C3 structure.
Figure 4: Interactions of the thioester and the TED domain.
Figure 5: The α′NT region (residues 727–744) slips through the β-ring.

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Acknowledgements

We acknowledge the help of beamline scientists of the EMBL/ESRF and in particular R. B. G. Ravelli for help in data collection, and A. Perrakis and D. Egan for help and use of their crystallization robots. We thank A. T. Brunger, M. Bowen, B. DeLaBarre, J. D. Lambris, C. W. Vogel, D. Fritzinger, T. Springer and T. K. Sixma for critically reading the manuscript. This work was supported by a ‘Pionier’ programme grant (P.G.) of the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW), the Dutch Kidney Foundation (A.R.), the Swedish Research Council (B.N.) and faculty grants at the University of Kalmar (K.N.-E.). A.R. does not support the evolutionary implications.

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Authors and Affiliations

  1. Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands

    Bert J. C. Janssen, Eric G. Huizinga, Hans C. A. Raaijmakers & Piet Gros

  2. Department of Nephrology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands

    Anja Roos & Mohamed R. Daha

  3. Department of Clinical Immunology, University Hospital, SE-751 85, Uppsala, Sweden

    Kristina Nilsson-Ekdahl & Bo Nilsson

  4. Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82, Kalmar, Sweden

    Kristina Nilsson-Ekdahl

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Correspondence to Piet Gros.

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Co-ordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 2A73 (C3) and 2A74 (C3c). Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure Legends

Figure captions for Supplementary Tables S1 and S2 and Supplementary Figures S1 to S6. (DOC 115 kb)

Supplementary Table S1

Diffraction data, structure solution and refinement statistics for C3c and C3. (PDF 51 kb)

Supplementary Table S2

Domain rotation and translation between C3 and C3c. (PDF 34 kb)

Supplementary Figure S1

Electron density of the α′NT region in C3c and the thioester in C3. (PDF 776 kb)

Supplementary Figure S2

Stereo representations of C3 and C3c. Secondary structure assignments and alignment of C3 with α2M family members. Structure-based sequence alignment of the eight MG domains of C3. Superposition of the eight MG domains of C3. (PDF 1190 kb)

Supplementary Figure S3

Structures of individual domains of C3 and C3c superposed. (PDF 1968 kb)

Supplementary Figure S4

Electrostatic surface potential of C3 and C3c. (PDF 217 kb)

Supplementary Figure S5

Sequence conservation of the β bridge, 205YVLP208, and the hinge 745FPES748. (PDF 387 kb)

Supplementary Figure S6

Conglutinin binding site and factor I cleavage sites in the CUB domain. (PDF 813 kb)

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Janssen, B., Huizinga, E., Raaijmakers, H. et al. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437, 505–511 (2005). https://doi.org/10.1038/nature04005

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