Factor B structure provides insights into activation of the central protease of the complement system |
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Authors: | Milder Fin J Gomes Lucio Schouten Arie Janssen Bert J C Huizinga Eric G Romijn Roland A Hemrika Wieger Roos Anja Daha Mohamed R Gros Piet |
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Institution: | Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. |
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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. |
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