title: Factor B structure provides insights into activation of the central protease of the complement system.
abstract: Factor B is the central protease of the complement system of immune defense. Here, we present the crystal structure of human factor B at 2.3-A resolution, which reveals how the five-domain proenzyme is kept securely inactive. The canonical activation helix of the Von Willebrand factor A (VWA) domain is displaced by a helix from the preceding domain linker. The two helices conformationally link the scissile-activation peptide and the metal ion-dependent adhesion site required for binding of the ligand C3b. The data suggest that C3b binding displaces the three N-terminal control domains and reshuffles the two central helices. Reshuffling of the helices releases the scissile bond for final proteolytic activation and generates a new interface between the VWA domain and the serine protease domain. This allosteric mechanism is crucial for tight regulation of the complement-amplification step in the immune response.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Fin J
authors.initials: FJ
authors.lastname: Milder
authors.forename: Lucio
authors.initials: L
authors.lastname: Gomes
authors.forename: Arie
authors.initials: A
authors.lastname: Schouten
authors.forename: Bert J C
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.forename: Roland A
authors.initials: RA
authors.lastname: Romijn
authors.forename: Wieger
authors.initials: W
authors.lastname: Hemrika
authors.forename: Anja
authors.initials: A
authors.lastname: Roos
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D020134:Catalytic Domain; D050577:Complement C3-C5 Convertases / Q000737:chemistry; D011415:Complement Factor B / Q000737:chemistry* / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000737:chemistry
chemical_list: D014841:von Willebrand Factor; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B