The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination1. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases1. Complement component 3 (C3) occupies a central position because of the manifold biological activities of its activation fragments, including the major fragment, C3b, which anchors the assembly of convertases effecting C3 and C5 activation. C3 is converted to C3b by proteolysis of its anaphylatoxin domain2, by either of two C3 convertases. This activates a stable thioester bond, leading to the covalent attachment of C3b to cell-surface or protein-surface hydroxyl groups through transesterification3. The cleavage and activation of C3 exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and viral molecules such as vaccinia virus complement-control protein4. C3b associates with these molecules in different configurations and forms complexes mediating the activation, amplification and regulation of the complement response1,4. Structures of C3 and C3c, a fragment derived from the proteolysis of C3b, have revealed a domain configuration, including six macroglobulin domains (MG1–MG6; nomenclature follows ref. 5) arranged in a ring, termed the β-ring5. However, because neither C3 nor C3c is active in complement activation and regulation, questions about function can be answered only through direct observations on C3b. Here we present a structure of C3b that reveals a marked loss of secondary structure in the CUB (for ‘complement C1r/C1s, Uegf, Bmp1’) domain, which together with the resulting translocation of the thioester domain provides a molecular basis for conformational changes accompanying the conversion of C3 to C3b. The total conformational changes make many proposed ligand-binding sites more accessible and create a cavity that shields target peptide bonds from access by factor I. A covalently bound N-acetyl-l-threonine residue demonstrates the geometry of C3b attachment to surface hydroxyl groups.
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We thank J. Chrzas for help with data measurement, K. Judge for technical assistance, the UAB Mass Spectroscopy Facility for mass spectra, and L. DeLucas for support. This research was supported by the NIH (H.M.K.M. and S.V.L.N.). G.J.K. is an International Senior Wellcome Trust Fellow for Biomedical Sciences in South Africa. Author Contributions K.G. and H.M.K.M. performed the crystallization and data measurement; A.A.A. and H.M.K.M. conducted the structure solution and refinement, and A.A.A., H.M.K.M., J.E.V., S.V.L.N. and G.J.K. performed the analysis.
A representation of the dynamics of C3 conversion to C3b and binding of the latter to microbial surfaces.
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