Factor B structure provides insights into activation of the central protease of the complement system

F.J. Milder, L. Gomes, A. Schouten, B.J.C. Janssen, E.G. Huizinga, R.A. Romijn, W. Hemrika, A Roos, M.R. Daha, P. Gros

Research output: Contribution to journalArticleAcademicpeer-review

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 complementamplification step in the immune response.
Original languageUndefined/Unknown
Pages (from-to)224-228
Number of pages5
JournalNature Structural and Molecular Biology
Volume14
Publication statusPublished - 2007

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