title: Structures of C3b in complex with factors B and D give insight into complement convertase formation.
abstract: Activation of the complement cascade induces inflammatory responses and marks cells for immune clearance. In the central complement-amplification step, a complex consisting of surface-bound C3b and factor B is cleaved by factor D to generate active convertases on targeted surfaces. We present crystal structures of the pro-convertase C3bB at 4 angstrom resolution and its complex with factor D at 3.5 angstrom resolution. Our data show how factor B binding to C3b forms an open "activation" state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which is cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Apostolia
authors.initials: A
authors.lastname: Tzekou
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Wallace
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D051561:Complement C3 Convertase, Alternative Pathway / Q000737:chemistry* / Q000378:metabolism; D003179:Complement C3b / Q000737:chemistry* / Q000378:metabolism; D011415:Complement Factor B / Q000737:chemistry* / Q000378:metabolism; D011416:Complement Factor D / Q000737:chemistry* / Q000378:metabolism; D003170:Complement Pathway, Alternative; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D050505:Mutant Proteins; D003179:Complement C3b; D011416:Complement Factor D; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B