title: Structures of complement component C3 provide insights into the function and evolution of immunity.
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 alpha2-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 alpha-chain, including movement of a critical interaction site through a ring formed by the domains of the beta-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Bert J C
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.forename: Hans C A
authors.initials: HC
authors.lastname: Raaijmakers
authors.forename: Anja
authors.initials: A
authors.lastname: Roos
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Kristina
authors.initials: K
authors.lastname: Nilsson-Ekdahl
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D003167:Complement Activation; D003176:Complement C3 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D015932:Complement C3c / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
chemical_list: D003176:Complement C3; D015932:Complement C3c; D050577:Complement C3-C5 Convertases