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-Å 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. © 2007 Nature Publishing Group.
Original language | English |
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Pages (from-to) | 224-228 |
Number of pages | 5 |
Journal | Nature structural & molecular biology |
Volume | 14 |
Issue number | 3 |
DOIs | |
Publication status | Published - 25 Feb 2007 |
Externally published | Yes |
Keywords
- catalytic domain
- complement C3-C5 convertases/chemistry
- complement factor B/chemistry
- complement system proteins/immunology
- crystallography, x-ray
- enzyme activation
- humans
- models, molecular
- protein structure, secondary
- protein structure, tertiary
- regulatory sequences, nucleic acid/genetics
- structure-activity relationship
- von Willebrand factor/chemistry