The structure of complement C3b provides insights into complement activation and regulation

• Published in: Nature 2006-11, Vol.444 (7116), p.221-225
• Main Authors: Abdul Ajees, A., Gunasekaran, K., Volanakis, John E., Narayana, Sthanam. V. L., Kotwal, Girish J., Krishna Murthy, H. M.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Biological and medical sciences; Complement Activation; Complement C3b - chemistry; Complement C3b - metabolism; Crystalline structure; Crystallography, X-Ray; Decay; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; Immunology; letter; Models, Molecular; Molecular biology; Molecular biophysics; multidisciplinary; Pathogens; Peptides; Protein Conformation; Proteins; Rats; Science; Science (multidisciplinary); Structure in molecular biology; Structure-Activity Relationship; Translocation; Vaccinia virus
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05258

Fishing for complement Three papers in this issue report the first X-ray structures of C3b, the active form of human complement C3. The complement system is a family of blood serum proteins and cell-surface receptors that recognizes pathogens and unleashes the immune response against them. The powerhouse of the C3 protein is a thioester group: when activated it binds to an acceptor on the pathogen and marks it for destruction. There are similar thioesters in host cells too, so the C3 thioester has to be kept tightly under wraps. Knowledge of the structure of the active form of C3b is a step towards designing therapies to manipulate the complement system. Inappropriate activation of the complement system has been implicated in various diseases including arthritis, asthma, lupus erythematosus, autoimmune heart disease and multiple sclerosis. The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination 1 . However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases 1 . 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 domain 2 , 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 transesterification 3 . 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 protein 4 . 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 β-ring 5 . However, because neither C3 nor C3c is active in complement activation and regulation, questions about function can be answered only through direct observation