title: Structure of complement fragment C3b-factor H and implications for host protection by complement regulators.
abstract: Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH enables proteolytic degradation of C3b by providing a binding platform for protease factor I while stabilizing the overall domain arrangement of C3b. Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: Bert J C
authors.initials: BJ
authors.lastname: Janssen
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D001665:Binding Sites; D003179:Complement C3b / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D046911:Macromolecular Substances; D003179:Complement C3b; D017242:Complement Factor H