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

Fin J Milder, Lucio Gomes, Arie Schouten, Bert J C Janssen, Eric G Huizinga, Roland A Romijn, Wieger Hemrika, Anja Roos, Mohamed R Daha, Piet 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-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 languageEnglish
Pages (from-to)224-228
Number of pages5
JournalNature structural & molecular biology
Volume14
Issue number3
DOIs
Publication statusPublished - 25 Feb 2007
Externally publishedYes

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

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