Factor B structure provides insights into activation of the central protease of the complement system.
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.
Milder
Fin J
FJ
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Gomes
Lucio
L
Schouten
Arie
A
Janssen
Bert J C
BJ
Huizinga
Eric G
EG
Romijn
Roland A
RA
Hemrika
Wieger
W
Roos
Anja
A
Daha
Mohamed R
MR
Gros
Piet
P
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
D014841:von Willebrand Factor; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B