1. Center for Biophysical Sciences and Engineering,
2. Department of Medicine, , 1530 3rd Avenue South, Birmingham, Alabama 35294, USA
3. Division of Medical Virology, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, HSC, Cape Town 7925, South Africa

Correspondence to: H. M. Krishna Murthy¹ Correspondence and requests for materials should be addressed to H.M.K.M. (Email: murthy@cbse.uab.edu). Coordinates and structure factors are deposited in the Protein Data Bank under accession number 2HR0.

Abstract

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 response^{1, 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 -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.

1. Center for Biophysical Sciences and Engineering,
2. Department of Medicine, , 1530 3rd Avenue South, Birmingham, Alabama 35294, USA
3. Division of Medical Virology, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, HSC, Cape Town 7925, South Africa

Correspondence to: H. M. Krishna Murthy¹ Correspondence and requests for materials should be addressed to H.M.K.M. (Email: murthy@cbse.uab.edu). Coordinates and structure factors are deposited in the Protein Data Bank under accession number 2HR0.

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