1. Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
2. Department of Nephrology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
3. Department of Clinical Immunology, University Hospital, SE-751 85 Uppsala, Sweden
4. Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden

Correspondence to: Piet Gros¹ Correspondence and requests for materials should be addressed to P.G. (Email: p.gros@chem.uu.nl). Co-ordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 2A73 (C3) and 2A74 (C3c).

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 2-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 -chain, including movement of a critical interaction site through a ring formed by the domains of the -chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.

1. Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
2. Department of Nephrology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
3. Department of Clinical Immunology, University Hospital, SE-751 85 Uppsala, Sweden
4. Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden

Correspondence to: Piet Gros¹ Correspondence and requests for materials should be addressed to P.G. (Email: p.gros@chem.uu.nl). Co-ordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 2A73 (C3) and 2A74 (C3c).

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